Nitrate salts of antimicrobial agents

ABSTRACT

Nitrate salts of antimicrobial agents for the preparation of antimicrobial medicaments, specifically antiviral, antifungal and antibacterial medicaments.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a National Stage entry of International Application No. PCT/EP01/00430, filed Jan. 16, 2001, the entire specification, claims and drawings of which are incorporated herewith by reference.

The present invention relates to compounds, or their pharmaceutical compositions, for systemic use and non, to be used in the antimicrobial therapy.

It is known that the wide use of antimicrobial agents in the infection treatment has caused the development of strains resistant to these drugs, for example the case of antiviral, antifungal and antibacterial agents can be mentioned.

This resistance generally arises when microorganisms develop growth and reproduction mechanisms on which the antimicrobial therapy is ineffective, or when the microorganisms produce enzymes which neutralize the drug. The resistant microbial strain is then able to multiply, causing the illness prolongation and worsening, with possible diffusion of the infection in the communities. This fact, as known, can determine notable consequences at a social-economic and sanitary level.

A method to solve this problem is to increase the dosage of the antimicrobial drugs. In this way there is the drawback of an increased incidence of side effects both local and systemic. Besides, cases of microbial superinfection deriving from the antimicrobial agent itself due to the inbalance between pathogen and non pathogen microbial flora often occur. It is well known that antimicrobial agents must act on the pathogen agents which are responsible of the unhealthy process and leave unaltered the non pathogen microbes useful for the organism.

A widely followed approach for solving the problem of the microbial resistance, and/or of the diffusion of pharmaco-resistant strains, has been to introduce in therapy new molecules to be used as antimicrobial agents. The results so far obtained are not satisfactory.

The need was therefore felt to have available drugs able not only to be active on the microorganism but also to prevent and/or reduce the microbial resistance and therefore to allow a complete and effective antimicrobial therapy, said drugs being effective at the conventional minimum dosages to avoid the side toxic effects. Among the latter skin rash and the effects on the stomach, liver and kidney can for example be mentioned.

It has been surprisingly and unexpectedly found by the Applicant that it is possible to solve the above technical problem by using compounds which have shown to be able to effectively interact with microbes and to prevent or reduce the microbial resistance.

An object of the present invention is the use of nitrate salts of antimicrobial agents, or their pharmaceutical compositions, for the preparation of medicaments usable in the treatment of infectious diseases. Preferably the invention relates to the use of nitrate salts of antiviral, antifungal and antibacterial agents, or their pharmaceutical compositions; the antimicrobial agents usable for preparing the nitrate salts of the present invention must satisfy the following test: in the culture of specific pathogen microbes responsible for the single pathologies, the antimicrobial agent is inoculated at a concentration such as to result effective as antimicrobial agent and such as not to produce cytotoxicity in mammalian cells.

See for example the test of the dilution in vitro on medium reported in the Examples for the antibacterial agents.

More specifically the present invention relates to the use of nitrate salts of compounds, or their pharmaceutical compositions, for preparing medicaments usable in the treatment of infectious diseases as antimicrobial agents, said compounds preferably being selected from the following classes:

class I)

wherein:

R₁=H, Cl or dimethylamino,

R₂=H, OH, or free valence,

R₃=H, CH₃, when R₂ is free valence with the doublet of the C—R₃ bond it forms a double bond and R₃ is methylene,

R₄=H, OH,

R₅=H, CH₂OH, or one of the following substituents:

class II)

wherein:

X and Y, different the one from the other, are C or N,

R₆=ciclopropyl, C₂H₅, 4-fluorophenyl, 2,4-difluorophenyl, 2-fluoroethyl,

R₇=H, amino, CH₃,

R₈=H or F, when Y=N, R₈ is free valence and it is the free doublet on the nitrogen atom,

R₉=H, CH₃ or one of the following substituents:

wherein M=H, CH₃, C₂H₅, OH,

wherein T₁ is H, OH

R₈ and R₉ taken together form the bivalent radical having formula: —O—CH₂—O— (IIP),

R₁₀=H, Cl, F, when X=N, R₁₀ is free valence and it is the free doublet on the nitrogen atom, R₆ and R₁₀ taken together form the following bivalent radicals:

when X in the formula (II)=N, R₁₀ is free valence and it forms a double bond with the carbon atom adjacent to the nitrogen;

class IIIa):

wherein:

Z=S, C,

R₁₁=H, pivaloyloxymethylene of formula (IIIaF) wherein T₂ is the tert-butyl group,

R₁₂=Cl, CH₃, acetyloxymethylene of formula (IIIaF) wherein T₂ is CH₃, 2-propenyl or one of the following substituents:

R₁₃=amino, OH, or the substituent (IIIaD):

R₁₄ is phenyl, 4-hydroxyphenyl, or the radical (IIIaE);

class IIIb)

wherein:

X=CH, N.

Y=C, N,

R₁₅=COOH, COO⁻, (CH₃)₃CCOOCH₂OCO— or (CH₃)₂CHOCOOCH(CH₃)OCO—,

R₁₆=H, CH₃, C₂H₅, —CH═CH₂, NH₂COOCH₂—, CH₃COOCH₂—, or one of the following substituents:

when R₁₅ is carboxylated anion R₁₆ is a radical selected from the following: (IIIbL), (IIIbM) or (IIIbN)

R₁₇=OH, OCH₃, C₂CH₅, —OCH₂COOH, —CH₂COOH;

class IIIc)

wherein:

R₁₈ is one of the following substituents:

R₁₉=H, CH₃COOCH₂—, or one of the following groups:

class IVa:

wherein:

R₂₀ is one of the following substituents:

R₂₁=H, the radical (IIIaF) with T₂=tert-butyl, CH(CH₃)OCOOC₂H₅ or one of the following substituents:

—CH₂CH₂N(CH₂CH₃)₂.HI  (IVaR),

class IVb)

wherein:

R₂₂=H, CH₃,

R₂₃ is selected from the following groups:

—CH₂CH₂NHCH═NH  (IVbD),

class IVc)

wherein:

R₃₃, R₃₄, R₃₆, equal to or different from each other, are H, CH₃;

R₃₅=H, —CH₂OCONH₂,

class V)

wherein

R₂₄=H, Br, OCH₃, CH₃OCH₂CH₂O—;

class VI)

wherein:

R₂₅ is one of the following substituents:

class VII)

wherein

R₂₆=H, or one of the following substituents: benzoyl, acetyl, 3-methyl-2-butenoyl, carbamoyl, aminothioxo NH₂C(S)— 2-pyridinyl, pyrazinyl, 2-pyrimidinyl, 2-thiazolyl, salicyl-4-yl, 6-chloro-pyridazine-3-yl, 1-ethyl-1,2-dihydro-2-oxo-pyrimidin-4-yl, 5,6-dimethoxy-pyrimidin-4-yl, 2,6-dimethoxy-Pyrimidin-4-yl, 4-methyl-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl, 6-methoxy-2-methyl-pyrimidin-4-yl, 5-methyl-pyrimidin-2-yl, 2,6-dimethyl pyrimidin-4-yl, 3-methoxy-pyrazine-2-yl, 6-methoxy-pyridazin-3-yl, 4,6-diethyl-1,3,5-triazin-2-yl, 5-ethyl-1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 4-methoxy-1,2,5-thiadiazol-3-yl, 4-methyl-thiazol-2-yl, 3-methyl-isothiazol-5-yl, 4,5-dimethyl-oxazol-2-yl, 3,4-dimethyl-isooxazol-5-yl, 4,5-dimethyl-2-oxazolylaminoiminomethyl, 5-methyl-isooxazol-3-yl, 1-phenyl-1H-pyrazol-5-yl, 4-methylamino sulphonylphenyl, 4-amino-sulphonylphenyl, 3,4-dimethylbenzoyl, 4-isopropoxy benzoyl;

class VIII)

wherein:

R₂₇=H, 4,6-dimethyl-pyrimidin-2-yl;

R₂₈=2,4-diamino-6-carboxyphenyl, 2,4-diaminophenyl, 3-car-boxy-4-hydroxyphenyl;

class IX)

wherein:

R₂₉=H, OH,

R₃₀=COOH, phenoxycarbonyl, 4-(amino)phenylsulphinyl, hydra-zinecarbonyl;

class X)

wherein:

R₃₁=amino, NH₂—CH₂—, benzylamino,

R₃₂=amino, 4-(hydroxyethylamino)phenyl, —N═C(NH₂)₂, 4-(amino)phenyl, 4-(aminomethyl) phenyl, 4-(carboxymethyl amino)phenyl, 4-(carboxypropionyl amino)phenyl, 2-amino-thiazol-5-yl;

class XI)

wherein:

M=O, S,

R₅₂=H, C₂H₅, C₃H₇,

R₅₃=amino, —NHNH₂, or one of the following substituents:

class XII)

wherein:

R₃₇=Cl, OH;

class XIIIa)

wherein:

R₃₈=H, acetyl, COC₂H₅ (propionyl),

R₃₉=H, propionyl, COC₃H₇ (butyryl), COCH₂CH(CH₃)₂ (isovaleryl),

R₄₀=H, propionyl,

R₄₁=H, or:

class XIIIb)

wherein:

R₄₇=H, CH₃,

W=CO (carbonyl), —N(CH₃)CH₂—,

R₄₈=H, or R₄₈ together with W forms the bivalent radical:

class XIVa)

wherein:

R₄₂=OH, amino,

R₄₃=H, (R)-4-amino-2-hydroxybutyryl, (S)-4-amino-2-hydroxybutyryl,

R₄₄=H, OH,

R₄₅=H, OH;

class XIVb)

wherein:

R₄₆=—CH₂OH; —CHO

Class XIVc)

wherein:

R₄₉=CH₃, C₄H₉;

class XIVd)

wherein:

R₅₀=H, C₂H₅,

R₅₁=3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl:

Class XIVe)

wherein:

R₆₀=OH, amino,

R₆₁=H or one of the following substituents:

Class XV)

wherein

R₅₄=CH₃, cyclopentyl;

Class XVIa)

wherein:

X_(b)=N, C,

R₅₅=H, amino,

R₅₆=H, OH, amino,

R₅₇ é β-D-ribofuranosyl or 4-acetoxy-3-(acetoxymethyl)1-bu-tyl;

Class XVIb)

wherein:

R₅₈=H, amino,

R₅₉=CH₂OCH₂CH₂OH, CH₂OCH(CH₂OH)CH₂OH, CH₂OCH₂CH₂OCOCH(NH₂)CH(CH₃)₂, β-D-(2,3-dideoxy)ribofuranosyl;

Class XVII): the following compounds:

O-2-amino-2-deoxy-α-D-glucopyranosyl-(1→4)-O-[3-deoxy-3-(methylamino)-α-D-xylopyranosyl-(1→6)]-2-deoxy-D-streptamine (Gentamycin A), 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazol (Metronidazole), (S)-2-amino-5-[(aminoiminomethyl)amino]pentanoic acid (Arginine), (+)-2,2′-(ethylendiimino)di-1-butanol (Ethambutol), 1-aminoadamantane (Amantadine), 2′,3′-dideoxy-cytidine (zalcitabine), Pyrazinamide, Morfazinamide, Acetylsulfamethoxypyrazine, Clofazimine, Cycloserine, Streptonicizid, Deoxydihydrostreptomycin, Mikamycin, Rosaramicin, Carbomycin, Alexidine, Ambazone, Cloxiquin, Negamycin, Nitroxoline, Porfiromycin, Taurolidine, Tibezonium iodide, Apramycin, Teicoplanin, Vancomycin, Thiabendazole, Mebendazole, Albendazole, Acranil, Anisomycin, Dimetridazole, Diminazene, Aceturate, Eflornithine, Halofuginone, Homidium, Hydroxystilbamidine, Imidocarb, Ipronidazole, Lauroguadine, Nimorazole, Oxophenarsine, Pentamidine, Phenamidine, Propamidine, Puromycin, Pyrimethamine, Quinacrine, Quinapyramine, Quintine, Secnidazole, Stilbamidine, Tinidazole.

In class I:

when R₁=H, R₂=OH, R₃=CH₃, R₄=H, R₅=(IA), the compound is known as Apicycline,

when R₁=Cl, R₂=OH, R₃=CH₃, R₄=H, R₅=H, the compound is known as Chlortetracycline,

when R₁=Cl, R₂=OH, R₃=CH₃, R₄=H, R₅=CH₂OH, the compound is known as Clomocycline,

when R₁=Cl, R₂=OH, R₃=H, R₄=H, R₅=H, the compound is known as Demeclocycline,

when R₁=H, R₂=H, R₃=CH₃, R₄=OH, R₅=H, the compound is known as Doxycycline,

when R₁=H, R₂=OH, R₃=CH₃, R₄=H, R₅=(IB), the compound is known as Guamecycline,

when R₁=H, R₂=OH, R₃=CH₃, R₄=H, R₅=(ID), the compound is known as Lymecycline,

when R₁=Cl, R₂=free valence and with the doublet of the C—R₃ bond it forms a double bond, and R₃ is methylene, R₄=OH, R₅=H, the compound is known as Meclocycline,

when R₁=H, R₂=free valence and with the doublet of the C—R₃ bond it forms a double bond, and R₃ is methylene, R₄=OH, R₅=H, the compound is known as Methacycline,

when R₁=dimethylamino, R₂=H, R₃=H, R₄=H, R₅=H, the compound is known as Minocycline,

when R₁=H, R₂=OH, R₃=H, R₄=OH, R₅=H, the compound is known as Oxytetracycline,

when R₁=H, R₂=OH, R₃=CH₃, R₄=H, R₅=(IC), the compound is known as Pipacycline,

when R₁=H, R₂=OH, R₃=CH₃, R₄=H, R₅=H, the compound is known as Tetracycline;

when R₁=H, R₂=H, R₃=H, R₄=H, R₅=H, the compound is known as Sancycline.

In class II:

when R₆=cyclopropyl, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=H, X=Y=C, the compound is known as Ciprofloxacin,

when R₆=cyclopropyl, R₇=H, R₈=F, R₉=(IIF), R₁₀=Cl, X=Y=C, the compound is known as Clinaloxacin,

when R₆=4-fluorophenyl, R₇=H, R₉=F, R₉=(IID), R₁₀=H, X=Y=C, the compound is known as Difloxacin,

when R₆=C₂H₅, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=free valence, X=N, Y=C, the compound is known as Enoxacin,

when R₆=cyclopropyl, R₇=H, R₈=F, R₉=(IIA) with M=C₂H₅, R₁₀=H, X=Y=C, the compound is known as Enrofloxacin,

when R₆=fluoroethyl, R₇=H, R₈=F, R₉=(IIA) with M=CH₃, R₁₀=F, X=Y=C, the compound is known as Fleroxacin,

when R₆ with R₁₀ forms the bivalent radical (IIM), R₇=H, R₈=F, R₉=H, X=Y=C, the compound is known as Flumequine,

when R₆=cyclopropyl, R₇=CH₃, R₈=F, R₉=(IIB), R₁₀=H, X=Y=C, the compound is known as Grepafloxacin,

when R₆=ethyl, R₇=H, R₈=F, R₉=(IIB), R₁₀=F, X=Y=C, the compound is known as Lomefloxacin,

when R₆ with R₁₀ forms the bivalent radical (IIM), R₇=H, R₈=F, R₉=(IIE) with T₁=OH, X=Y=C, the compound is known as Nadifloxacin,

when R₆=C₂H₅, R₇=H, R₈=H, R₉=CH₃, R₁₀=free valence, X=N, Y=C, the compound is known as Nalidixic acid,

when R₆=C₂H₅, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=H, X=Y=C, the compound is known as Norfloxacin,

when R₆ with R₁₀ forms the bivalent radical (IIN), R₇=H, R₈=F, R₉=(IIA) with M=CH₃, X=Y=C, the compound is known as Ofloxacin,

when R₆=C₂H₅, R₇=H, R₈ and R₉ form the bivalent radical (IIP), R₁₀=H, X=Y=C, the compound is known as Oxolinic acid,

when R₆ with R₁₀ forms the bivalent radical (IIO), R₇=H, R₈=F, R₉=(IIH), X=Y=C, the compound is known as Pazufloxacin,

when R₆=ethyl, R₇=H, F, R₉=(IIA) with M=CH₃, R₁₀=H, X=Y=C, the compound is known as Pefloxacin,

when R₆=C₂H₅, R₇=H, R₈=free valence, R₉=(IIA) with M=H, R₁₀=free valence, X=Y=N, the compound is known as Pipeimidic acid,

when R₆=C₂H₅, R₇=H, R₈=free valence, R₉=(IIE) with T₁=H, R₁₀=fre valence, X=Y=N, the compound is known as Piromidic acid,

when R₆ with R₁₀ forms the bivalent radical (IIQ), R₇=H, R₈=F, R₉=(IIA) with M=CH₃, X=Y=C, the compound is known as Rufloxacin,

when R₆=cyclopropyl, R₇=amino, R₈=F, R₉=(IIC), R₁₀=F, X=Y=C, the compound is known as Sparfloxacin,

when R₆=2,4-difluorophenyl, R₇=H, R₈=F, R₉=(IIF), R₁₀=free valence, X=N, Y=C, the compound is known as Tosufloxacin,

when R₆=2,4-difluorophenyl, R₇=H, R₈=F, R₉=(IIG), R₁₀=free valence, X=N, Y=C, the compound is known as Trovafloxacin,

when R₆=cyclopropyl, R₇=H, R₈=F, R₉=(IID), R₁₀=H, X=Y=C, the compound is known as Danofloxacin,

when R₆=4-fluorophenyl, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=H, X=Y=C, the compound is known as Sarafloxacin.

In class IIIa:

when R₁₁=H, R₁₂=Cl, R₁₃=amino, R₁₄=phenyl, Z=S, the compound is known as Cefaclor,

when R₁₁=H, R₁₂=CH₃, R₁₃=amino, R₁₄=4-hydroxyphenyl, Z=S, the compound is known as Cefafroxil,

when R₁₁=H, R₁₂=(IIIaB), R₁₃=amino, R₁₄=4-hydroxyphenyl, Z=S, the compound is known as Cefatrizine,

when R₁₁=H, R₁₂=(IIIaC), R₁₃=(IIIaD), R₁₄=4-hydroxyphenyl, Z=S, the compound is known as Cefpiramide,

when R₁₁=H, R₁₂=2-propenyl, R₁₃=amino, R₁₄=4-hydroxyphenyl, Z=S, the compound is known as Cefprozil,

when R₁₁=H, R₁₂=CH₃, R₁₃=amino, R₁₄=(IIIaE), Z=S, the compound is known as Cefroxadine,

when R₁₁=H, R₁₂=CH₃, R₁₃=amino, R₁₄=phenyl, Z=S, the compound is known as Cephalexin,

when R₁₁=H, R₁₂=CH₃, R₁₃=(IIIaF) with T₂=CH₃, R₁₄=phenyl, Z=S, the compound is known as Cephaloglycin,

when R₁₁=H, R₁₂=CH₃, R₁₃=amino, R₁₄=(IIIaE), Z=S, the compound is known as Cephadrine,

when R₁₁=H, R₁₂=Cl, R₁₃=amino, R₁₄=phenyl, Z=C, the compound is known as Loracarbef,

when R₁₁=(IIIaF) with T₂=tert-butyl, R₁₂=CH₃, R₁₃=amino, R₁₄=phenyl, Z=S, the compound is known as Pivcefalexin,

when R₁₁=H, R₁₂=(IIIaC), R₁₃=OH, R₁₄=phenyl, Z=S, the compound is known as Cefamandole.

In class IIIb:

when R₁₅=(CH₃)₃CCOOCH₂OCO—, R₁₆=NH₂COOCH₂—, R₁₇=C₂H₅, X=CH, Y=C, the compound is known as Cefcapene Pivoxil,

when R₁₅=COO⁻, P₁₆=(IIIbL), R₁₇=methoxyl, X=Y=N, the compound is known as Cefclidin,

when R₁₅=COOH, R₁₆=—CH=CH₂, R₁₇=OH, X=N, Y=C, the compound is known as Cefdinir,

when R₁₅=COOH, R₁₆=(IIIbA), R₁₇=OCH₃, X=N, Y=C, the compound is known as Cefditoren,

when R₁₅=COO⁻, R₁₆=(IIIbM), R₁₇=OCH₃, X=N, Y=C, the compound is known as Cefepime,

when R₁₅=COOH, R₁₆=CH₃, R₁₇=OCH₃, X=N, Y=C, the compound is known as Cefetamet,

when R₁₅=COOH, R₁₆=—CH=CH₂, R₁₇=—OCH₂OCOOH, X=N, Y=C, the compound is known as Cefixime,

when R₁₅=COOH, R₁₆=(IIIbC), R₁₇=OCH₃, X=N, Y=C, the compound is known as Cefmenoxime,

when R₁₅=COO⁻, R₁₆=(IIIbN), R₁₇=OCH, X=Y=N, the compound is known as Cefozopran,

when R₁₅=(CH₃)₂CHOCOOCH(CH₃)OCO—, R₁₆=C₂H₅, R₁₇=OCH₃, X=N, Y=C, the compound is known as Cefpodoxime Proxetil,

when R₁₅=COOH, R₁₆=(IIIbD), R₁₇=OCH₃, X=N, Y=C, the compound is known as Cefteram,

when R₁₅=COOH, R₁₆=H, R₁₇=—CH₂COOH, X=CH, Y=C, the compound is known as Ceftibuten,

when R₁₅=COOH, R₁₆=(IIIBH), R₁₇=OCH₃, X=N, Y=C, the compound is known as Ceftriaxone,

when R₁₅=COOH, R₁₆=(IIIbE), R₁₇=OCH₃, X=N, Y=C, the compound is known as Cefuzonam,

when R₁₅=COOH, R₁₆=(IIIbF), R₁₇=OCH₃, X=N, Y=C, the compound is known as Cefodizime,

when R₁₅=COOH, R₁₆=CH₃COOCH₂—, R₁₇=OCH₃, X=N, Y=C, the compound is known as Cefotaxime,

when R₁₅=COOH, R₁₆=(IIIbG), R₁₇=OCH₃, X=N, Y=C, the compound is known as Ceftiofur.

In class IIIc:

when R₁₈=(IIIcD), R₁₉=(IIIcH), the compound is known as Cefotiam,

when R₁₈=(IIIcE), R₁₉=H, the compound is known as Ceftizoxime,

when R₁₈=(IIIcF), R₁₉=(IIIcN), the compound is known as Cefazolin,

when R₁₈=(IIIcG), R₁₉=(IIIcM), the compound is known as Ceforanide,

when R₁₈=(IIIcA), R₁₉=(IIIcL), the compound is known as Cefminox,

when R₁₈=(IIIcB), R₁₉=CH₃COOCH₂—, the compound is known as Cephalosporin C.

In Class IVa:

when R₂₀=(IVaF) and R₂₁=H, the compound is known as Amdinocillin,

when R₂₀=(IVaF) and R₂₁=(IIIaF) with T₂=tert-butyl, the compound is known as Amdinocillin Pivoxil,

when R₂₀=(IVaA) and R₂₁=H, the compound is known as Amoxicillin,

when R₂₀=(IVaB) and R₂₁=H, the compound is known as Ampicillin,

when R₂₀=(IVaM) and R₂₁=H, the compound is known as Apalcillin,

when R₂₀=(IVaG) and R₂₁=H, the compound is known as Aspoxicillin,

when R₂₀=(IVaB) and R₂₁=—CH(CH₃)OCOOC₂H₅, the compound ia known as Bacampicillin,

when R₂₀=(IVaE) and R₂₁=H, the compound is known as Cyclacillin,

when R₂₀=(IVaC) and R₂₁=H, the compound is known as Epicillin,

when R₂₀=(IVaC) and R₂₁=H, the compound is known as Hetacillin,

when R₂₀=(IVaC) and R₂₁=(IVaS), the compound is known as Lenampicillin,

when R₂₀=(IVa) and R₂₁=H, the compound is known as Mezlocillin,

when R₂₀=(IVaD) and R₂₁=(IVaR), the compound is known as Penethamate Hydroiodide,

when R₂₀=(IVaP) and R₂₁=H, the compound is known as Penicillin N,

when R₂₀=(IVaB) and R₂₁=(IIIaF) with T₂=tert-butyl, the compound is known as Pivampicillin,

when R₂₀=(IVaN) and R₂₁=H, the compound is known as Quinacillin,

when R₂₀=(IVaB) and R₂₁=(IVaU), the compound is known as Sultamicillin,

when R₂₀=(IVaB) and R₂₁=(IVaT), the compound is known as Talampicillin.

In class IVb:

when R₂₂=CH₃, R₂₃=(IVbA), the compound is known as Meropenem,

when R₂₂=H, R₂₃=(IVbC), the compound is known as Panipenem,

when R₂₂=H, R₂₃=(IVbD), the compound is known as Imipenem.

In class IVc:

when R₂₃=CH₃, R₃₄=CH₃, R₃₅=H, R₃₆=CH₃, the compound is known as Aztreonam,

when R₃₃=H, R₃₄=H, R₃₅=—CH₂OCONH₂, R₃₆=H, the compound is known as Carumonam.

In class V:

when R₂₄=Br, the compound is known as Brodimoprim,

when R₂₄=OCH₃, the compound is known as Trimethoprim,

when R₂₄=CH₃OCH₂CH₂O—, the compound is known as Tetroxoprim.

In class VI:

when R₂₅=(VID) the compound is known as Furaltadone,

when R₂₅=(VIC) the compound is known as Furazolium chloride,

when R₂₅=(VIE) the compound is known as Nifurfoline,

when R₂₅=(VIA) the compound is known as Nifurpirinol,

when R₂₅=(VIB) the compound is known as Nifurprazine.

In class VII:

when R₂₆=H, the compound is known as Sulfanilamide,

when R₂₆=benzoyl, the compound is known as Sulfabenzamide,

when R₂₆=acetyl, the compound is known as Sulfacetamide,

when R₂₆=3-methyl-2-butenoyl, the compound is known as Sulfadicramide,

when R₂₆=carbamoyl, the compound is known as Sulfanilylurea,

when R₂₆=NH₂C(S)—, the compound is known as Sulfathiourea,

when R₂₆=2-pyridinyl, the compound is known as Sulfapyridine,

when R₂₆=pyrazinyl, the compound is known as Sulfapyrazine,

when R₂₆=2-pyrimidinyl, the compound is known as Sulfadiazine,

when R₂₆=2-thiazolyl, the compound is known as Sulfathiazole,

when R₂₆=salicyl-4-yl, the compound is known as 4-sulphanilamido salicylic acid,

when R₂₆=6-chloro-pyridazinyl-3-yl, the compound is known as Sulfachlorpyridazine,

when R₂₆=1-ethyl-1,2-dihydro-2-oxo-pyrimidin-4-yl, the compound is known as Sulfacytine,

when R₂₆=5,6-dimethoxy-pyrimidin-4-yl, the compound is known as Sulfadoxine,

when R₂₆=2,6-dimethoxy-pyrimidin-4-yl, the compound is known as Sulfadimethoxine,

when R₂₆=4-methyl-pyrimidin-2-yl, the compound is known as Sulfamerazine,

when R₂₆=5-methoxy-pyrimidin-2-yl, the compound is known as Sulfameter,

when R₂₆=4,6-dimethyl-pyrimidin-2-yl, the compound is known as Sulfamethazine

when R₂₆=6-methoxy-2-methyl-pyrimidin-4-yl, the compound is known as Sulfamethomidine,

when R₂₆=5-methyl-pyrimidin-2-yl, the compound is known as Sulfaperine,

when R₂₆=2,6-dimethylpyrimidin-4-yl, the compound is known as Sulfisomidine,

when R₂₆=3-methoxy-pyrazin-2-yl, the compound is known as Sulfalene,

when R₂₆=6-methoxy-pyridazin-3-yl, the compound is known as Sulfamethoxypyridazine,

when R₂₆=4,6-diethyl-1,3,5-triazin-2-yl, the compound is known as Sulfasymazine,

when R₂₆=5-ethyl-1,3,4-thiadiazol-2-yl, the compound is known as Sulfaethidole,

when R₂₆=5-methyl-1,3,4-thiadiazol-2-yl, the compound is known as Sulfamethizole,

when R₂₆=4-methoxy-1,2,5-thiadiazol-3-yl, the compound is known as Sulfametrole,

when R₂₆=4-methyl-thiazol-2-yl, the compound is known as Sulfamethylthiazole,

when R₂₆=3-methyl-isothiazol-5-yl, the compound is known as Sulfasomizole,

when R₂₆=4,5-dimethyl-oxazol-2-yl, the compound is known as Sulfamoxole,

when R₂₆=3,4-dimethy-isoxazol-5-yl, the compound is known as Sulfisoxazole,

when R₂₆=4,5-dimethyl-2-oxazolylaminoiminomethyl, the compound is known as Sulfaguanol,

when R₂₆=5-methyl-isoxazol-3-yl, the compound is known as Sulfamethoxazole,

when R₂₆=1-phenyl-1H-pyrazol-5-yl, the compound is known as Sulfaphenazole,

when R₂₆=4-methylamino sulphonylphenyl, the compound is known as 4′-(methylsulfamoyl)sulfanilanilide,

when R₂₆=4-aminosulphonylphenyl, the compound is known as N⁻⁴ sulfanilylsulfanilamide,

when R₂₆=3,4-dimethylbenzoyl, the compound is known as N-sulfanyl-3,4-xylamide,

when R₂₆=4-isopropoxybenzoyl, the compound is known as Sulfaproxyline.

In class VIII:

when R₂₇=H, R₂₈=2,4-diamino-6-carboxyphenyl, the compound is known as Sulfachrysoidine,

when R₂₇=H, R₂₈=2,4-diaminophenyl, the compound is known as Sulfamidochrysoidine,

when R₂₇=4,6-dimethyl-pyrimidin-2-yl, R₂₈=3-carboxy-4-hydroxyphenyl, the compound is known as Salazo sulfadimidine.

In class IX:

when R₂₉=OH, R₃₀=COOH, the compound is known as p-Aminosalicylic acid,

when R₂₉=OH, R₃₀=hydrazinecarbonyl, the compound is known as p-Aminosalicylhydrazide,

when R₂₉=OH, R₃₀=phenoxycarbonyl, the compound is known as Phenylaminosalicylate,

when R₂₉=H, R₃₀=4-(amino)phenylsulphinyl, the compound is known as 4,4′-Sulphinyldianiline.

In class X:

when R₃₁=amino, R₃₂=4-(hydroxyethylamino)phenyl, the compound is known as 2-p-Sulfanilylanilino ethanol,

when R₃₁=amino, R₃₂=—N=C(NH₂)₂, the compound is known as Sulfaguanidine,

when R₃₁=NH₂CH₂—, R₃₂=amino, the compound is known as Mafenide,

when R₃₁=benzylamino, R₃₂=amino, the compound is known as Benzylsulfamide,

when R₃₁=amino, R₃₂=4-(carboxymethylamino)phenyl, the compound is known as Acediasulfone,

when R₃₁=amino, R₃₂=4-(amino)phenyl, the compound is known as Dapsone,

when R₃₁=amino, R₃₂=4-(carboxypropionylamino)phenyl, the compound is known as Succisulfone,

when R₃₁=amino, R₃₂=4-(aminomethyl)phenyl, the compound is known as p-Sulfanilylbenzylamine,

when R₃₁=amino, R₃₂=2-amino-thiazol-5-yl, the compound is known as Thiazolsulfone.

In class XI:

when R₅₂=C₂H₅, R₅₃=amino, M=S, the compound is known as Ethionamide,

when R₅₂=H, R₅₃=—NHNH₂, M=O, the compound is known as Isoniazid,

when R₅₂=C₃H₇, R₅₃=amino, M=S, the compound is known as Protionamide,

when R₅₂=H, R₅₃=(XIA), M=O, the compound is known as Sulfoniazide,

when R₅₂=H, R₅₃=(XIB), M=O, the compound is known as Verazide,

when R₅₂=H, R₅₃=(XIC), M=O, the compound is known as Opiniazide,

when R₅₂=H, R₅₃=(XID), M=O, the compound is known as Salinazid,

when R₅₂=H, R₅₃=(XIE), M=O, the compound is known as Furonazide,

when R₅₂=H, R₅₃=(XIF), M=O, the compound is known as Glyconiazide.

In class XII:

when R₃₇=Cl, the compound is known as Clindamycin,

when R₃₇=OH, the compound is known as Lincomycin.

In class XIIIa:

when R₃₈=acetyl, R₃₉=isovaleryl, R₄₀=H, R₄₁=H, the compound is known as Josamycin,

when R₃₈=propionyl, R₃₉=propionyl, R₄₀=H, R₄₁=H, the compound is known as Midecamycin A₁,

when R₃₈=H, R₃₉=butyryl, R₄₀=propionyl, R₄₁=H, the compound is known as Rokictamycin,

when R₃₈=H, R₃₉=H, R₄₀=H, R₄₁=(XIIIaB), the compound is known as Spiramycin I,

when R₃₈=acetyl, R₃₉=H, R₄₀=H, R₄₁=(XIIIaB), the compound is known as Spiramycin II,

when R₃₈=propionyl, R₃₉=H, R₄₀=H, R₄₁=(XIIIaB), the compound is known as Spiramycin III,

when R₃₈=H, R₃₉=isovaleryl, R₄₀=H, R₄₁=H, the compound is known as Leucomycin.

In class XIIIb:

when R₄₇=H, R₄₈=H, W=—N(CH₃)CH₂—, the compound is known as Azithromycin,

when R₄₇=CH₃, R₄₈=H, W=carbonyl, the compound is known as Clarithromycin,

when R₄₇=H, R₄₈=H, W=carbonyl, the compound is known as Erythromycin,

when R₄₇=H, R₄₈ and W for together (XIIIbA), the compound is known as Dirithromycin.

In class XIVa:

when R₄₂=OH, R₄₃=(S)-4-amino-2-hydroxybutyryl, R₄₄=OH, R₄₅=OH, the compound is known as Amikacin,

when R₄₂=amino, R₄₃=(R)-4-amino-2-hydroxy butyryl, R₄₄=H, R₄₅=H, the compound is known as Arbekacin,

when R₄₂=amino, R₄₃=H, R₄₄=H, R₄₅=H, the compound is known as Dibekacin,

when R₄₂=amino, R₄₃=H, R₄₄=OH, R₄₅=H, the compound is known as Tobramycin.

In class XIVb:

when R₄₆=—CH₂OH, the compound is known as Dihydrostreptomycin,

when R₄₆=—CHO, the compound is known as Streptomycin.

In class XIVc:

when R₄₉=CH₃, the compound is known as Spectinomycin,

when R₄₉=C₄H₉, the compound is known as Trospectomycin.

In class XIVd:

when R₅₀H, R₅₁=(XIVdA), the compound is known as Micronomicin,

when R₅₀=C₂H₅, R₅₁=3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl, the compound is known as Netilmicin,

when R₅₀=H, R₅₁=3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl, the compound is known as Sisomicin.

In class XIVe:

when R₆₀=amino, R₆₁=(XIVeA) the compound is known as Neomycin,

when R₆₀=OH, R₆₁=(XIVed) the compound is known as Paromycin,

when R₆₀=amino, R₆₁=H, the compound is known as Ribostamycin.

In class XV:

when R₅₄=CH₃, the compound is known as Rifampin,

when R₅₄=cyclopentyl, the compound is known as Rifapentine.

In class XVIa:

when X_(b)=N, R₅₅=H, R₅₆=OH, R₅₇=β-D-ribofuranosyl, the compound is known as Inosine,

when X_(b)=N, R₅₅=amino, R₅₆=H, R₅₇=4-acetoxy-3-(acetoxymethyl)1-butyl, the compound is known as Famcyclovir,

when X_(b)=C, R₅₅=H, R₅₆=amino, R₅₇=β-D-ribofuranosyl, the compound is known as Tubercidin.

In class XVIb:

when R₅₈=H, R₅₉=β-D-(2,3-dideoxy)ribo furanosyl, the compound is known as Didanosine,

when R₅₈=amino, R₅₉=CH₂OCH₂CH₂OH, the compound is known as Acyclovir,

when R₅₈=amino, R₅₉=CH₂OCH₂CH₂OCOCH(NH₂)CH(CH₃)₂, the compound is known as Valacyclovir,

when R₅₈=amino, R₅₉=CH₂OCH(CH₂OH)CH₂OH, the compound is known as Gancyclovir.

The following compounds are preferred:

In class I:

when R₁=H, R₂=H, R₃=CH₃, R₄=OH, R₅=H, the compound is known as Doxycycline,

when R₁=H, R₂=OH, R₃=H, R₄=OH, R₅=H, the compound is known as Oxytetracycline,

when R₁=H, R₂=OH, R₃=CH₃, R₄=H, R₅=H, the compound is known as Tetracycline.

In class II:

when R₆=cyclopropyl, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=H, X=Y=C, the compound is known as Ciprofloxacin,

when R₆=C₂H₅, R₇=H, R₈=H, R₉=CH₃, R₁₀=free valence, X=N, Y=C, the compound is known as Nalidixic acid,

when R₆=C₂H₅, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=H, X=Y=C, the compound is known as Norfloxacin,

when R₆ with R₁₀ form the bivalent radical (IIN), R₇=H, R₈=F, R₉=(IIA) with M=CH₃, X=Y=C, the compound is known as Ofloxacin.

In class IIIa:

when R₁₁=H, R₁₂=Cl, R₁₃=amino, R₁₄=phenyl, Z=S, the compound is known as Cefaclor,

when R₁₁=H, R₁₂=CH₃, R₁₃=amino, R₁₄=phenyl, Z=S, the compound is known as Cephalexin,

when R₁₁=H, R₁₂=(IIIaC), R₁₃=OH, R₁₄=phenyl, Z=S, the compound is known as Cefamandole.

In class IIIb:

when R₁₅=COOH, R₁₆=ethenyl, R₁₇=—OCH₂OCOOH, X=N, Y=C, the compound is known as Cefixime,

when R₁₅=(CH₃)₂CHOCOOCH(CH₃)OCO—, R₁₆=C₂H₅, R₁₇=OCH₃, X=N, Y=C, the compound is known as Cefpodoxime Proxetil,

when R₁₅=COOH, R₁₆=(IIIbF), R₁₇=OCH₁, X=N, Y=C, the compound is known as Cefodizime.

In class IIIc:

when R₁₈=(IIIcF), R₁₉=(IIIcN), the compound is known as Cefazolin.

In class IVa:

when R₂₀=(IVaA) and R₂₁=H, the compound is known as Amoxicillin,

when R₂₀=(IVaB) and R₂₁=H, the compound is known as Ampicillin,

when R₂₀=(IVaM) and R₂₁=H, the compound is known as Apalcillin.

In class IVb:

when R₂₂=H, R₂₃=(IVbD), the compound is known as Imipenem.

In class IVc:

when R₃₃=CH₃, R₃₄=CH₃, R₃₅=H, R₃₆=CH₃, the compound is known as Aztreonam.

In class V:

when R₂₄=OCH₃, the compound is known as Trimethoprim.

In class VI:

when R₂₅=(VIE) the compound is known as Nifurfoline.

In class VII:

when R₂₆=5-methyl-isoxazol-3-yl, the compound is known as Sulfamethoxazole.

In class X:

when R₃₁=amino, R₃₂=4-(amino)phenyl, the compound is known as Dapsone.

In class XI:

when R₅₂=C₂H₅, R₅₃=amino, M=S, the compound is known as Ethionamide;

when R₅₂=H, R₅₃=—NHNH₂, M=O, the compound is known as Isoniazid.

In class XIIIb:

when R₄₇=H, R₄₈=H, W=—N(CH₃)CH₂—, the compound is known as Azithromycin,

when R₄₇=H, R₄₈=H, W=carbonyl, the compound is known as Erythromycin,

when R₄₇=CH₃, R₄₈=H, W=carbonyl, the compound is known as Clarithromycin.

In class XIVa:

when R₄₂=OH, R₄₃=(S)-4-amino-2-hydroxybutyryl, R₄₄=OH, R₄₅=OH, the compound is known as Amikacin,

when R₄₂=amino, R₄₃=H, R₄₄=OH, R₄₅=H, the compound is known as Tobramycin.

In class XIVb:

when R₄₆=—CHO, the compound is known as Streptomycin.

In class XIVc:

when R₄₉=CH₃, the compound is known as Spectinomycin.

In class XIVd:

when R₅₀=C₂H₅, R₅₁=3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl, the compound is known as Netilmicin.

In class XIVe:

when R₆₀=amino, R₆₁=(XIVeA) the compound is known as Neomycin.

In class XV:

when R₅₄=CH₃, the compound is known as Rifampin.

In class XVIa:

when X_(b)=N, R₅₅=H, R₅₆=OH, R₅₇=β-D-ribofuranosyl, the compound is known as Inosine,

when X_(b)=N, R₅₅=amino, R₅₆=H, R₅₇=4-acetoxy-3-(acetoxymethyl)1-butyl, the compound is known as Famcyclovir.

In class XVIb:

when R₅₈=H, R₅₉=β-D-(2,3-dideoxy)ribo furanosyl, the compound is known as Didanosine,

when R₅₈=amino, R₅₉=CH₂OCH₂CH₂OH, the compound is known as Acyclovir,

when R₅₈=amino, R₅₉=CH₂OCH₂CH₂OCOCH(NH₂)CH(CH₃)₂, the compound is known as Valacyclovir,

when R₅₈=amino, R₅₉=CH₂OCH(CH₂OH)CH₂OH, the compound is known as Gancyclovir.

In class XVII:

O-2-amino-2-deoxy-α-D-glucopyranosyl-(1→4)-O-[3-deoxy-3-(methylamino)-α-D-xylopyranosyl-(1→6)]-2-deoxy-D-streptamine (Gentamycin A), (S)-2-amino-5-[(aminoiminomethyl)amino]pentanoic acid (Arginine), (+)-2,2′-(ethylendiimino)di-1-butanol (Ethambutol), 1-amino adamantan (Amantadine), 2′,3′-dideoxy-cytidine (zalcitabine), Pyrazinamide, Morphazinamide, Teicoplanin, Vancomycin, Metronidazole

A further object of the invention are also the nitrate salts compounds of antimicrobial, preferably antiviral, antifungal and antibacterial agents, or their pharmaceutical compositions, for the preparation of medicaments, excluding the nitrate salts of Erythromycin, Isoniazid, Pyrazinamide, Metronidazole, Acyclovir.

In the present invention can be used also the nitrate salts of the corresponding nitrooxy derivatives of the above listed antimicrobic agents, said nitrooxy derivatives characterized in that in their molecules there are one or more, preferably one, substituents having the general formula (I-N)

—B—(W)_(p)—ONO₂  (I-N)

wherein:

p is 1 or 0;

B=—T_(B)—Y—_(BI)— wherein T_(B) e T_(BI) are same or different;

T_(B) is a chemical function covalently linked to the chemical or reactive function of the drug molecule and is (CO) or X, wherein X=O, S, NH, with the condition that X=(CO) when the reacting function of the drug is OH or NH₂ or SH; T_(B) is X when the reacting function of the drug is a carboxyl group;

T_(BI)=(CO)_(tx) or (X)_(txx), wherein tx and tax are 0 or 1; with the condition that tx=1 when txx=0, tx=0 when txx=1; X is as above defined;

Y is a bivalent linking bridge chosen between the following structures:

wherein:

nIX is an integer comprised between 0 and 3, preferably is 1;

nIIX is an integer comprised between 0 and 3, preferably is 1;

R_(TIX), R_(TIX′), R_(TIIX), R_(TIIX′), same or different each from the other, are H or linear or branched C₁-C₄ alkyl;

preferably R_(TIX), R_(TIX′), R_(TIIX′), are H.

Y³ is a ring containing at least one salifiable nitrogen atom; preferably Y is an heterocyclic ring containing one or two nitrogen atoms, the ring saturated, unsaturated or aromatic, having preferably 5 or 6 atoms.

An alkylene group R′ wherein R′ is a linear or branched C₁-C₂₀ alkyl, preferably a C₂-C₆ alkyl, optionally substituted with one or more of the following groups: —NHCOR_(3Y), wherein R_(3Y) is a linear or branched C₁-C₅ alkyl, —NH₂, —OH;

A cycloalkylene ring C₅-C₇, optionally substituted with R′, being R′ as above defined, wherein one or more C atoms of the cycloalkylene can be optionally substituted with heteroatoms;

 wherein n3 is an integer from 0 to 3 and n3′ is an integer from 1 to 3;

 wherein n3 and n3′ have the meanings above indicated;

 wherein:

R_(4Y) is OH, H, alcoxy R_(5Y)O— wherein R_(5Y) is a linear or branched or cyclo C₁-C₁₀ alkyl, preferably R_(5Y) is methyl;

R_(2Y) is a linear or branched alkenylene C₂-C₁₀ containing one or more double bonds, preferably R_(2Y) is an ethenylene group (—CH═CH—);

wherein R_(1f)=H, CH₃ and nf is an integer from 0 to 6;

preferably from 0 to 4;

W of formula (I-N) is the bivalent radical —T_(c)—Y_(T)-wherein:

T_(c)=(CO) when t_(x)=0, T_(c)=X when t_(xx)=0;

with the proviso that in formula (I-N) when p=1 Y_(T) is different from Y and in the bivalent radical B:

Y is R′ as above defined having a substituent NHCOR_(3Y), preferably R′ is a C₂ saturated alkyl and R_(3Y) is CH₃; T_(a)=S; T_(B1) is —CO—; preferably Y is —CH₂—CH(NHCOCH₃)— and B in formula (I-N) preferably has the following structure:

 or

Y is a bivalent radical of formula (V-Y), wherein R_(4Y) is OR_(5Y) and R_(5Y) is preferably CH₃, R_(2Y) is the group —CH═CH—; preferably Y has the following formula

Preferably Y³ in formula (II-Y) is selected from the following bivalent radicals:

Preferably Y³ is a 6-membered aromatic ring containing one nitrogen atom, said ring having the two free valences in the following positions: 2,6; 2,3; 2,5.

The preferred of Y³ is Y12 (pirydil) substituted at positions 2 and 6.

Y1 (pyrazole) can be 3,5-disubstituted.

A further object of the present invention are the nitrate salts of the nitrooxy derivatives of the antimicrobial above listed compounds, preferably having antiviral, antifungal and antibacterial activity, or their pharmaceutical compositions, for the preparation of medicaments, excluding the nitrate salts of the nitrooxy derivatives of Erythromycin, Isoniazid, Pyrazinamide, Metronidazole, Acyclovir when in formula (I-N) p=0.

The derivatives of antibacterial agents having in their molecules one or more of the substituencs of formula (I-N) can be prepared according to methods known in the art.

In general, if in the molecule of the drug, or in the bivalent radicals B or W of formula (I-N) there are more than one reactive groups COOH and/or Hx, X being as above defined, said reactive groups must be protected before the reaction according to the methods known in the art; for example as described in the volume by Th. W. Greene: “Protective groups in organic synthesis”, Harward University Press, 1980.

Acyl halides are prepared according to the methods known in the prior art, for example by thionyl or oxalyl chloride, P^(III) or P^(V) halides in inert solvents under the reaction conditions, such as for example toluene, chloroform, DMF, etc.

1) When the reactive chemical function of the drug is a carboxyl group and p=0 in formula (I-N), the corresponding nitrooxy derivatives can be prepared by the following methods:

1.a) The acid RCOOH (wherein R is the drug radical) and an halogen alcohol derivative of formula HO—Y—Hal, wherein Y is as above defined and Hal is an halogen atom, for example Cl, Br, Iodine, may be coupled to produce the ester of formula (1/C) by treatment with a de-hydrating agent such as N,N′-carbonyldiimidazol (CDI), N-hydroxy-benzotriazol, and dicyclohexylcarbodiimide (DCC) in the presence of a condensation catalyst such as 4-dimethylaminopyridine (DMAP), in a solvent such as for example DMF, THF, chloroform etc. at a temperature in the range from −5° C. to 50° C.

1.b) Alternatively the acid RCOOH may first be converted into an alkali metal salt such as sodium or potassium salt and reacted with a dihalogenated derivative of general formula Y(Hal)₂, wherein Y and Hal are as above defined.

R—COONa+Hal—Y—Hal-------->R—CO—O—Y—Hal  (1/B)

1.c) Alternatively the acid may first be converted to the acyl chloride of formula R—CO—Cl (wherein R is the drug radical) and then is reacted with an halogena alcohol of formula HO—Y—Hal or a dial of formula HO—Y—OH, wherein y is as above defined and Hal is halogen (Cl, Br, I):

R—COCl+HO—Y—Hal-------->R—CO—O—Y—Hal  (1/A)

R—COCl+HO—Y—HO-------->R—CO—C—Y—OH  (1/A′)

1.d) The acid RCOOH and a dihalogenide compound of formula Hal—Y—Hal, wherein Y and Hal are as above defined, may be coupled to form an ester in the presence of a base, in an organic solvent inert in the reaction conditions according to the following scheme:

RCOHal+Hal—Y—Hal---→R—COO—Y—Hal  (1/D)

1.e) When the compounds obtained in the herein above described reactions have formula R—COO—Y—Hal, the corresponding nitrooxyderivatives are obtained by reacting the compound R—CO—O—Y—Hal with AgNO₃ in an organic solvent such as acetonitrile, tetrahydrofuran according to the following scheme:

R—COO—Y—Hal+AgNO₃-------→R—COO—Y—ONO₂

1.f) When the compounds obtained in the herein above described reactions have the formula R—COO—Y—OH, the hydroxy group is firstly halogenated, for instance by means of PBr₃, PCl₅, SOCl₂, PPh₃+I₂, then reacted with AgNO₃ in an organic solvent such as acetonitrile, tetrahydrofuran.

2) When in formula (I-N) p=0, and the free valence of R is saturated with an hydroxy group, the methods of synthesis of the corresponding nitrooxy derivatives are the following:

2.a) The drug of formula R—OH and an halogenoacid of formula Hal—Y—COOH or an hydroxyacid of formula HO—Y—COOH, wherein Y and Hal are as above defined, may be coupled according to the reactions known in the art to produce the esters of formula (2/A) or (2/B), according to the following schemes:

R—OH—Hal—Y—COCl-----→R—OCO—Y—Hal  (2/A)

R—OH—Hal—Y—COCl-----→R—OCO—Y—OH  (2/B)

2.b) When the compounds obtained in the herein above described reactions have the formula R—OCO—Y—Hal or R—OCO—Y—OH, the corrresponding nitrooxy derivatives are obtained as described in 1.f and 1.e respectively.

3. When in formula (I-N) p=1 and the reactive group of the drug molecule is a carboxyl group, the methods of synthesis for obtaining the corresponding nitrooxy derivatives are the following ones:

3.a) The drug of formula RCOOH may first be converted to the acyl chloride of formula R—CO—CL (wherein R is the drug radical) and then is reacted with a compound of formula HX—Y—COOH according to the methods known in the art, to obtain a compound of formula R—CO—X—Y—COOH, that it is converted into the corresponding sodium salt and then reacted with a compound of formula Hal—YT—RY wherein Hal e Y_(T) are as above defined and R_(BY) is Cl, Br, Iodine, OH:

R—COHal+HX—Y—COOH---→R—CO—X—Y—COOH  (3.A)

R—CO—X—Y—COONa+Hal—Y_(T)—R₈---→R—CO—X—Y—CO—Y_(T)—R₈  (3.A′)

 When R_(8Y)=OH, the compound of formula (3.A′) is halogenated as above described in 1.f); when R_(8Y)=Hal the compound of formula (3.A′) is reacted with AgNO₃ in an organic solvent such as acetonitrile, tetrahydrofuran:

3.b) When Y_(T) is a linear alkylene C₄, the acid compound of formula (3.A) is reacted with triphenylphosphine in the presence of an halogenating agent such as CBr₄ or N-bromosuccinimide in tetrahydrofuran to give directly the compound of formula (3.A′) wherein R_(BY)=Br, said compound is then converted into the corresponding nitrooxy derivative as described under i.e.

4) When in formula (I-N) p=1 and the reactive group of the antibacterian drug is an hydroxy group, the methods of synthesis for obtaining the corresponding nitrooxy derivatives are the following ones:

4.a) The drug of formula R—OH and an acyl halogenide of formula HX—Y—COHal wherein Y, X and Hal are as above defined, may be coupled according to the methods known in the art to produce the ester of formula of formula R—O—CO—Y—XH (4/A), that is then reacted with a compound of formula R_(8Y)—Y_(T)—COHal wherein R_(8Y) and Y_(T) are as above defined.

R—OH+HX—Y—COCl---→R—O—CO—Y—XH  (4/A)

R—O—CO—Y—XH+R₈—Y_(TY)CO—Hal--→R—O—CO—Y—X—CO—Y_(T)—R_(8Y)  (4A′)

4.b) Alternatively, the drug R—OH is reacted with a compound of formula HX—Y—COOH, wherein X and Y are as above defined, in the presence of dicyclohexylcarbodiimide as described under 1.a, to obtain a compound of formula R—O—CO—Y—XH, that is then reacted with a compound of formula R_(8Y)—Y_(T)—COCl wherein R_(8Y) and Y_(T) are as above defined, to give the following compound: R—O—CO—Y—X—CO—Y_(T)—R_(8Y) (4/B) When R_(8Y)=OH the compound corresponding to the formula (4/B) or (4a′) is halogenated as above described under 1.f); when R₈=Hal the compound of formula (4/B) is reacted with AgNO₃ in an organic solvent such as acetonitrile, tetrahydrofuran.

The nitrooxy derivatives of the antibacterian agent can also by prepared according to the synthetic methods described in WO 95/30641 herein incorporated by reference.

In the salts or their compositions according to the present invention also one or more isomers, including optical isomers, when possible, of the above described antimicrobial compounds can be used.

The nitrate salts according to the present invention contain at least one nitrate ion mole/compound mole. Preferably the ratio nitrate ion moles/precursor moles is unitary. Salts having a higher molar ratio are obtained when in the molecule more aminic groups, sufficiently basic to be able to be salified, are present.

The salts of the present invention are formulated in the corresponding pharmaceutical compositions according to well known techniques in the prior art, together with the usual excipients; see for example the volume “Remington's Pharmaceutical Sciences 15a Ed.”

The precursors of the salts belonging to the above mentioned classes are prepared according to the methods described in the Merck Index 14a Ed., herein incorporated by reference.

The nitrate salts of the antibacterial compounds are prepared by the following methods.

When the compound to be salified is available as free base soluble in an organic solvent, which preferably does not contain hydroxyl groups, for example acetonitrile, ethyl acetate, tetrahydrofuran, etc., the salt is prepared by dissolving the compound in the solvent at a concentration preferably equal to or higher than 10% w/v, adding the amount of concentrated nitric acid corresponding to the moles of salifiable aminic groups present in the compound. The nitric acid is preferably diluted in the same solvent. Preferably during and after the addition it is cooled at temperatures in the range 0° C.-20° C.

The product is generally recovered by filtration and washed with the solvent.

When the compound is not very soluble, or it is available under the form of a not very soluble salt in the above mentioned solvents, the corresponding mixtures with hydroxylated solvents can be used. Examples of such solvents are methyl alcohol, ethyl alcohol and water. The precipitation of the nitrate salt can be accelerated by diluting then the so obtained mixture, after the addition of nitric acid, with an apolar solvent.

When the starting compound is salified with hydrochloric acid, it is possible to prepare the nitrate salt by directly adding silver nitrate to the compound solution. After having filtered the silver chloride, the solution is concentrated and cooled for recovering the nitrate salt.

When the starting compound is a salt, the corresponding base can also be released by treatment with a saturated solution of sodium or potassium bicarbonate or carbonate, or with a diluted solution of sodium or potassium hydroxide. The base is then extracted with a suitable organic solvent (for example halogenated solvents, esters, ethers), which is then dried. The organic solution is evaporated and one proceeds according to the previous preparation methods, by dissolving the base in acetonitrile or in the other above mentioned solvents.

The compounds and compositions of the present invention can be used for systemic applications, for example they can be administered by os with formulations known in the prior art such as for example tablets or capsules, or by parenteral route, such as for example by intravenous or intramuscular administration in formulations in sterile apyrogenic physiological solution, optionally additioned with other excipients known in the prior art.

It is possible to use the nitrate salts of the present invention for topical applications, under the form of gels or creams, or by aerosol (by inhalation).

As said, the compounds of the invention are used in the therapy of the same pathologies for which the precursor antimicrobial agents ar used. However since the products of the invention show an improved activity, they can be used even at lower doses. This is advantageous since it allows to avoid the side effects mentioned above for precursors.

The following Examples are given with the only purpose to illustrate the invention and they are not limitative of the same.

EXAMPLES Preparation Examples Example 1

Preparation of the Cefalexine Nitrate Salt

A solution of Cefalexine hydrochloride (3 g, 13.02 mmoles) in a mixture of acetonitrile (150 ml) and tetrahydrofuran (150 ml) is treated with silver nitrate (2.22 g, 13.06 mmoles) sheltered from the light. It is left under stirring for 30 minutes at room temperature, then the silver chloride is filtered and the solution is concentrated at a reduced pressure up to the half of the initial volume. Ethyl ether (100 ml) is added and, after cooling at 5° C., the obtained solid is filtered. After drying 4.3 g of Cefalexine nitrate salt as amorphous solid are obtained. Yield 80%.

Elementary analysis for C₁₆H₁₈N₄O₇S Calculated %: C 46.83; H 4.42; N 13.65; S 7.81 Found %: C 46.81; H 4.44; N 13.63; S 7.80

Example 2

Preparation of the Clindamycin Nitrate Salt

The compound is prepared by starting from a solution of Clindamycin hydrochloride (3 g, 6.5 mmoles) in ethanol (100 ml) by addition of silver nitrate (1.12 g, 6.59 mmoles) and following the procedure reported in Example 1. Clindamycin nitrate salt as amorphous solid is obtained. Yield 70%.

Elementary analysis for C₁₈H₃₄ClN₃O₈S: Calculated %: C 44.30; H 7.02; Cl 7.26; N 8.61; S 6.57 Found %: C 44.32; H 7.03; Cl 7.23; N 8.62; S 6.55

Example 3

Preparation of the Amoxicillin Nitrate Salt

The compound is prepared starting from a solution of Amoxicillin hydrochloride (2 g, 4.98 mmoles) in a mixture of acetonitrile (80 ml)/tetrahydrofuran (80 ml) by addition of silver nitrate (0.850 g, 5.0 mmoles), following then the procedure reported in Example 1. Amoxicillin nitrate as amorphous solid is obtained. Yield 78%.

Elementary analysis for C₁₆H₂₀N₄O₈S: Calculated %: C 44.86; H 4.71; N 13.08; S 7.48 Found %: C 44.89; H 4.74; N 13.11; S 7.45

Example 4

Preparation of the Tetracycline Nitrate Salt

The compound is prepared by starting from a solution of Tetracycline hydrochloride (2 g, 4.16 mmoles) in methanol (100 ml) by adding silver nitrate (0.71 g, 4.17 mmoles), and following then the procedure reported in Example 1. Tetracycline nitrate salt as amorphous solid is obtained. Yield 60%.

Elementary analysis for C₂₂H₂₅N₃O₁₁: Calculated %: C 52.07; H 4.97; N 8.28; Found %: C 52.05; H 4.99; N 8.30;

Example 5

Preparation of the Clarithromycin Nitrate Salt

To a solution of Clarithromycin (2 g, 2.67 mmoles) in a mixture of acetonitrile (50 ml) and chloroform (80 ml), cooled at 0° C., a 65% HNO₃ solution (0.2 ml) in acetonitrile (5 ml) is added. After the addition the mixture is let reach the room temperature and it is maintained under stirring for two hours. The solvent is evaporated at a reduced pressure. The residue is dissolved in chloroform (50 ml) and ethyl ether (50 ml) is added. It is cooled at 5° C. and the precipitate which separates is filtered. After drying 1.83 g (2.26 mmoles) of Clarithromycin nitrate salt as amorphous solid are obtained. Yield 80%.

Elementary analysis for C₃₈H₇₈N₂O₁₆: Calculated %: C 56.28 H 8.70 N 3.45 Found %: C 56.25 H 8.72 N 3.46

Example 6

Preparation of the Ciprofloxacin Nitrate Salt

Triethylamine (0.9 ml, 6.5 mmoles) is added to a suspension of Ciprofloxacin hydrochloride (2 g, 5.4 mmoles) in 200 ml of methylene chloride. The solution is maintained under stirring for 30 minutes. The solution is washed with water (100 ml), the organic phase is dried by sodium sulphate and then evporated under vacuum obtaining the corresponding Ciprofloxacin base (1.03 g). The substance is dissolved in a mixture of acetonitrile (60 ml)/tetra-hydrofuran (50 ml). The solution is cooled with ice and treated with a solution (0.220 ml) of 656 nitric acid in acetonitrile (5 ml). After 30 minutes under cold stirring it is treated with ethyl ether. A solid is separated which is filtered, washed with ethyl ether and dried under vacuum. 1.2 g of Ciprofloxacin nitrate salt as amorphous solid are obtained. Yield 45%.

Elementary analysis for C₁₇H₁₉N₄O₆F: Calculated %: C 51.78; H 4.86; N 14.21; F 4.82 Found %: C 51.75; H 4.84; N 14.25; F 4.80

Example 7

Preparation of the Sulfamethoxazole Nitrate Salt

The compound is prepared by starting from a Sulfamethoxazole solution (2 g, 7.9 mmoli) in methanol (100 ml), addition of a 65% nitric acid solution (0.500 ml) in acetonitrile (5 ml), following the procedure reported in Example 5. Sulfamethoxazole nitrate as amorphous solid is obtained. Yield 60%.

Elementary analysis for C₁₀H₁₂N₄O₆S: Calculated %: C 37.97; H 3.82; N 17.71; S 10.15 Found %: C 37.99; H 3.83; N 17.73; S 10.13

Example 8

Preparation of the Trimethoprim Nitrate Salt

The compound is synthetized starting from a solution of Trimethoprim (1.5 g, 5.17 mmoles) in chloroform (80 ml), by adding a 65% nitric acid solution (0.360 ml) in acetonitrile (5 ml) and following then the procedure described in Example 5. Trimethoprim nitrate salt as amorphous solid is obtained. Yield 60%.

Elementary analysis for C₁₄H₁₉N₅O₆: Calculated %: C 47.59 H 5.42 N 19.82 Found %: C 47.57 H 5.44 N 19.83

Example 9

Preparation of the Pyrazinamide Nitrate Salt

The compound is prepared starting from a solution of Pyrazinamide (2 g, 16.24 mmoles) in a mixture of acetonitrile (30 ml)/tetrahydrofuran (30 ml), by adding a 65% nitric acid solution (1.2 ml) in acetonitrile (5 ml), following then the procedure described in Example 5. Pyrazinamide nitrate salt as amorphous solid is obtained. Yield 74%.

Elementary Analysis for C₅H₆N₄O₄: Calculated %: C 32.27 H 3.25 N 30.10 Found %: C 32.29 H 3.24 N 30.13

Example 10

Preparation of the Nifurfoline Nitrate Salt

The compound is prepared starting from a Nifurfoline solution (1 g, 2.96 mmoles) in a mixture of tetrahydrofuran (20 ml)/acetonitrile (20 ml), by adding a 65% nitric acid solution (0.210 ml) in acetonitrile (3 ml), and following then the procedure described in Example 5. Nifurfoline nitrate salt as amorphous solid is obtained. Yield 55%.

Elementary analysis for C₁₃H₁₆N₆O₉: Calculated %: C 39.01 H 4.03 N 20.99 Found %: C 32.03 H 4.05 N 21.01

Example 11

Preparation of Acyclovir Nitrate Salt

The compound is prepared starting from an Acyclovir solution (1 g, 4.44 mmoles) in a mixture of tetrahydrofuran (20 ml)/acetonitrile (20 ml), by adding a 65% nitric acid solution (0.310 ml) in acetonitrile (5 ml), and following then the procedure described in Example 5. Acyclovir nitrate salt as amorphous solid is obtained. Yield 60%.

Elementary analysis for C₈H₁₂N₆O₆: Calculated %: C 33.34 H 4.20 N 29.17 Found %: C 33.31 H 4.22 N 29.19

Example 12

Preparation of Metronidazole Nitrate Salt

The compound is prepared starting from a metronidazole solution (1 g, 5.84 mmoles) in a mixture of tetrahydrofuran (10 ml)/acetonitrile (15 ml) and by adding a 65% nitric acid solution (0.410 ml) in acetonitrile (3 ml), following then the procedure described in Example 5. Metronidazole nitrate salt as amorphous solid is obtained. Yield 70%.

Elementary analysis for C₆H₁₀N₄O₆: Calculated %: C 30.77 H 4.30 N 24.03 Found %: C 30.74 H 4.28 N 24.01

Example 13

Preparation of Erythromycin Nitrate Salt

The compound is prepared starting from an erythromycin solution (2 g, 2.72 mmoles) dissolved in a mixture of chloroform (30 ml)/acetonitrile (20 ml), by adding a 65% nitric acid solution (0.200 ml) in acetonitrile (5 ml), following then the procedure described in Example 5. Erythromycin nitrate as amorphous solid is obtained. Yield 83%.

Elementary analysis: Calculated %: C 55.76 H 8.59 N 3.51 Found %: C 55.79 H 8.60 N 3.53

Example 14

Preparation of the Cefazolin Nitrate Salt

The compound is prepared by adding to a Cefazolin solution (1.5 g, 3.3 mmoles) in methanol (50 ml) a 65% nitric acid solution (0.250 ml) in acetonitrile (5 ml) and following then the procedure reported in Example 5. Cefazolin nitrate as amorphous solid is obtained. Yield 60%.

Elementary Analysis for C₁₄H₁₅N₉O₇S₃: Calculated: C 32.49; H 2.92; N 24.36; S 18.59 Found: C 32.48; H 2.94; N 24.37; S 18.57

Example 15

Preparation of the Ampicillin Nitrate Salt

The compound is prepared startaing from an Ampicillin solution (2 g, 5.72 rmoles) in a mixture formed by acetonitrile (30 ml) and tetrahydrofuran (20 ml), by adding a 65% nitric acid solution (0.450 ml) in acetonitrile (5 ml) and following the procedure reported in Example 5. Ampicillin nitrate as amorphous solid is obtained. Yield 55%.

Elementary analysis for C₁₆H₂₀N₄O₇S: Calculated: C 46.60; H 4.89; N 13.58; S 7.77 Found: C 46.56; H 5.91; N 13.59; S 7.76

Pharmacological Examples

Dilution Test in vitro on Medium for Antibacterial Agents

The capability to antagonize the arising of the microbial resistance of the nitrate salts of the antimicrobial compounds in comparison with that of the respective precursors has been evaluated.

Such activity has been determined by using the dilution method in vitro on culture medium as described by Sahm et al. (S. D. Sahm, J. A. Washington “Antibacterial susceptibility tests: dilution methods” in: Manual of Clinical Microbiology, ed. A. Balows, W. J. Hausler, Jr, K. L. Hermann, H. D. Isenberg, H. J. Shadomy, 1991, American Society for Microbiology). According to this method a concentration in aqueous solution of substance having antimicrobial activity able to inhibit the growth of some bacterial strains is determined. For the precursor the maximum concentration of the substance at which the microbial growth is still observed under the adopted experimental conditions is selected and the same concentration is used for the corresponding nitrate salt. The solvents and the necessary dilutions for preparing the strain substances of the antibiotics to be tested are prepared according to procedures standard and well known to the man skilled in the field (National Committee for Clinical Laboratory Standards, 1990 “Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A2. National Committee for Clinical Laboratory Standards, Villanova, Pa.). Also the preparation of the culture medium is carried out according to standard procedures and the CAMH broth is used (Cation-adjusted Mueller-Hinton broth) (National Committee for Clinical Laboratory Standards, 1990, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A2. National Committee for Clinical Laboratory Standards, Villanova, Pa.).

The inoculation procedure is carried out according to standard procedures and the final concentration of the inocolum is of 5×10⁵ CFU (colony forming unit)/ml. The used microorganisms have been Escherichia Coli (ATCC25922) and Staphylococcus Aureus (ATCC29213).

The test tubes are incubated at 35° C. for 20 hr before reading. The microbial growth, or the absence of the same, is determined in a qualitative way, with the naked eye and it indicates the microbial resistance or, respectively, the sensitivity to the antimicrobial agent. The results of the tests are reported in Tables 1 and 2, which show that the nitrate salt has an antimicrobial activity higher than that of the precursor.

Example 16

Synthesis of 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolincarboxylic acid 4-nitrooxybutyl ester nitrate salt

A) Synthesis of 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-N-tert-butoxycarbonyl-1-piperazinyl)-4-oxo-3-quinolincarboxylic acid 4-bromobutyl ester

To a stirred solution of 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolincarboxylic acid hydro chloride (504.14 mg, 1.3 mmoles) in 1,4-dioxane (2.6 ml) and NaOH 2M (1,3 ml), was added di-tert-butyl dicarbonate (306 mg, 1.4 mmoles) at 0° C. After stirring for 2 hours the suspension was filtered and the precipitate washed with 1,4-dioxane, dried to afford 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-N-tert-butoxycarbonyl-1-piperazinyl)-4-oxo-3-quinolincarboxylic acid that was used without further purification.

To a suspension of 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-N-tert-butoxycarbonyl-1-piperazinyl)-4-oxo-3-quinolin carboxylic acid and NaHCO₃ (11 mg, 1.3 mmoles) in DMF (10 ml) was added 1,4-dibromobutane (1.4 g, 6.5 mmoles).

The mixture was refluxed for 1 hour and, after cooling, were added in the order water and ethyl acetate. After separation of the phases the organic layer was washed with water, dried with sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate/n-hexane (v/v 2/1) to afford 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-N-tert-butoxy carbonyl-1-piperazinyl)-4-oxo-3-quinolineecarboxylic acid 4-bromobutyl ester (380 mg, 0.65 mmoles) as an amorphous solid. Yield 50%.

B) Synthesis of 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolincarboxylic acid 4-nitrooxybutyl ester

To a solution of 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-N-tert-butoxycarbonyl-1-piperazinyl)-4-oxo-3-quinolin carboxylic acid 4-nitrooxybutyl ester (300 mg, 0.51 mmoles) in anhydrous acetonitrile (5 ml) was added silver nitrate (170 mg, 1 mmoles). The mixture was refluxed for 4 hours in the darkness.

The suspension was filtered and the filtrate washed with water (3×8 ml) and dried with sodium sulphate, then evaporated in vacuo.

The compound was deprotected by treating with trifluoroacetic acid (1 ml) at room temperature, in an inert atmosphere (N₂), for 1 hour. Trifluoroacetic acid was removed by evaporation under a reduced pressure and the residue was purified by chromatography on a weakly basic ion-exchange resin (Amberlyst® A-21) eluting with ethyl acetate to afford 1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolin carboxylic acid 4-nitrooxybutyl ester (150 mg, 0.32 mmoles) as an amorphous solid.

¹NMR (ppm): 8.25 (1H, s); 7.85 (1H, d); 4.52 (2H, t); 4.5-4.2 (4H, m); 3.4-2.8 (7H, m); 1.94-1.83 (4H, m); 1.48 (3H, m); 1.06 (3H, d).

C) Synthesis of 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolincarboxylic acid 4-nitrooxybutyl ester nitrate salt

To a solution of 1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolincarboxylic acid 4-nitrooxy butyl ester (150 mg, 0.32 mmoles) in CH₂Cl₂ (2 ml) was added HCl—AcOEt 1 M (0.5 ml). After stirring for 1 hours at room temperature, the solvent was evaporated under reduced pressure and the residue dissolved in THF (4 ml) and silver nitrate (55 mg, 3.03 mmoles) was added. The mixture was stirred for 1 hour at room temperature, the suspension was filtered and the precipitate washed with THF, dried to afford 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolin carboxylic acid 4-nitrooxybutyl ester nitrate salt (150 mg) as an amorphous solid. Yield 88%.

Elementary Analysis: % C % H % N % F calculated: 47.46 5.12 13.18 7.15 found: 47.50 5.10 13.10 7.20

Example 17

Synthesis of 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid 4-nitrooxybutyl ester nitrate salt

A) Synthesis of 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(N-tert-butoxy carbonyl-1-piperazinyl-)-3-quinolinecarboxylic acid 4-bromobutyl ester

To a solution of 1-Ethyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolincarboxylic acid hydro chloride (2.5 g, 7.8 mmoles) and KOH 2M (11.7 ml) in 1,4-dioxane (15 ml) was added di-tert-butyl dicarbonate (1.75 g, 8 mmoles), at −4° C. The mixture was stirred for 1 hour at 0° C., thereafter the cooling bath was removed and stirred until the temperature was risen to room temperature (about 1 hour). Water (15 ml) was added and, after cooling, the mixture was filtered and the precipitate was dried to afford 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(N-tert-butoxycarbonyl-1-piperazinyl-)-3-quinoline carboxylic acid, that was used without further purification.

To a suspension of 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(N-tert-butoxycarbonyl-1-piperazinyl-)-3-quinolinecarboxylic acid and 18-crown-6 (1,4,7,10,13-pentaoxacyclopentadecane) in anhydrous THF (20 ml) was added 1,4-dibromobutane (1.4 g, 6.5 mmoles) in an inert atmosphere (N₂).

The mixture was refluxed for 1 hour and, after cooling, water and ethyl acetate were added in the order.

After separation of the phases, the organic layer was washed with water, dried with sodium sulphate and evaporated Under reduced pressure.

The residue was purified by chromatography on silica gel eluting with ethyl acetate/n-hexane (v/v 2/1) to afford 1-Ethyl-6-fluoro-1,4-dihydro-7-(3-methyl-N-tert-butoxycarbonyl-1-pipera zinyl)-4-oxo-3-quinolinecarboxylic acid 4-bromobutyl ester 380 mg, 0.65 mmoles) as an amorphous solid. Yield 66%.

B) Synthesis of 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pipera zinyl)-3-quinolinecarboxylic acid 4-nitrooxybutyl ester nitrate salt

To a solution of 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(N-tert-butoxycarbonyl-1-piperazinyl-)-3-quinolincarboxylic acid 4-nitrooxybutyl ester (443.5 mg, 0.8 mmoles) in anhydrous acetonitrile (7 ml) was added silver nitrate (406 mg, 0.8 mmoles). The mixture was refluxed for 5 hours in the darkness, in an inert atmosphere (N₂). The suspension was filtered, the filtrate was evaporate in vacuo. The residue was dissolved in CH₂Cl₂ (10 ml; and the mixture was washed with water (5×10 ml) and anhydrified with sodium sulphate, the solvent was then evaporated under reduced pressure.

The compound was deprotected with trifluoroacetic acid (1.6 ml) at room temperature, in an inert atmosphere (N₂) for 1 hour. Trifluoroacetic acid was evaporated under reduced pressure and the residue was purified by chromatography on a weakly basic ion-exchange resin (Amberlyst® A-21) eluting with methanol to afford 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid 4-nitrooxybutyl ester nitrate (306 mg, 0.7 mmoles) as a yellow amorphous solid.

¹H NMR (DMSO) ppm: 7.39 (5H, d); 7.03 (8H, d); 5.96 (2H, B); 4.58 (2H, m); 4.38 (2H, m); 4.18 (2H, m); 3.33 (4H, m); 3.16 (4H, m); 1.94-1.83 (4H, m); 1.8-1.86 (4H, m); 1.35 (3H, t).

C) Synthesis of 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pipera zinyl)-3-quinolinecarboxylic acid 4-nitrooxybutyl ester nitrate salt

To a solution of 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid 4-nitrooxybutyl ester (300 mg, 0.68 mmoles) in CH₂Cl₂ (5 ml) was added HCl—AcOEt 1 M (0.8 ml). After stirring for 1 hour at room temperature, the solvent was evaporated under a reduced pressure. The residue was dissolved in THF (10 ml) and silver nitrate (120 mg, 0.70 mmoles) was added. The mixture was stirred for 1 hour at room temperature, the suspension was filtered and the precipitate washed with THF and dried to afford 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid 4-nitrooxybutyl ester nitrate salt (300 mg) as an amorphous solid. Yield 85%.

Elementary Analysis: % C % H % N % F calculated: 48.10 5.25 14.02 3.80 found: 48.05 5.30 14.11 3.75

Example 18

Synthesis of 3-[[4-[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarbonyloxy]-3-methoxy]phenyl]-2-propenoic acid 4-(nitrooxybutyl)butyl ester nitrate salt

A) Synthesis of 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(N-tert-butoxycarbonyl-1-piperazinyl-)-3-quinolinecarboxylic acid

To a suspension of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl-)-3-quinolinecarboxylic acid (3.31 g, 10 mmoles) in CH₂Cl₂ (120 ml) were added at room temperature TEA (4.21 ml, 30 mmoles) and di-tert-butyl dicarbonate (4.4 g, 30 mmoles). The mixture was stirred for 12 hours at room temperature. After cooling at −5° C. the suspension was filtered, the collected precipitate dissolved in CH₂Cl₂ (200 ml) and the resulting solution washed with aq AcOH 0.3 M (100 ml)

The organic phase was dried with sodium sulphate and the solvent was evaporated in vacuo. The residue was crystallized from a mixture CH₂Cl₂ (10 ml)/n-hexane (100 ml) to afford 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(N-tert-butoxy carbonyl-1-piperazinyl-)-3-quinolinecarboxylic acid (3.93 g). Yield 91% m.p. 248-249° C. (dec.)

B) Synthesis of 3-[[4-[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(N-tert-butoxycarbonyl-1-piperazinyl)-3-quinolinecarbonyloxy]-3-methoxy]phenyl]-2-propenoic acid 4-(nitrooxybutyl)butyl ester

To a solution of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(N-tert-butoxycarbonyl-1-piperazinyl-)-3-quinolinecarboxylic acid (5.36 g, 12.43 mmoles) and of 3-[(3-methoxy-4-hydroxy)phenyl]-2-propenoic acid 4-nitrooxybutyl ester (3.78 g, 12.43 mmoles) in CH₂Cl₂ (100 ml) Ph₃P (4.89 g, 18.64 mmoli) and DEAP (2.94 ml, 18.64 mmoli) were added in the order. The mixture was stirred for 2 hours at room temperature, then the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH₂Cl₂/acetone (v/v 30/1) to afford 3-[4-[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(N-tert-butoxycarbonyl-1-piperazinyl)-3-quinolinecarbonyloxy]-3-methoxy]2-propenoic acid 4-(nitrooxybutyl)butyl ester (3.5 g). Yield 40%.

C) Synthesis of 3-[4-[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarbonyloxy]-3-methoxy]2-propenoic acid 4-(nitrooxybutyl)butyl ester hydrochloride

To a solution of 3-[4-[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(N-tert-butoxycarbonyl-1-piperazinyl)-3-quinoline carbonyloxy]-3-methoxy]2-propenoic acid 4-(nitrooxybutyl)butyl ester (3.5 g) in CH₂Cl₂ (50 ml) was added HCl—AcOEt 20% (5 ml). After stirring for 2 hours at room temperature, the solvent was evaporated under a reduced pressure and the residue was dissolved in acetone (40 ml). After cooling at 0° C. for 30 minutes, the suspension was filtered and the collected precipitate washed with diethyl ether to afford 3-[4-[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarbonyloxy]-3-methoxy]2-propenoic acid 4-(nitrooxy butyl) butyl ester hydrochloride (2 g) as a yellow solid. m.p. 207-209° C.

¹H NMR (DMSO) ppm: 9.26 (1H, S), 8.68 (1H, S), 7.85 (1H, d), 7.68 (1H, d), 7.53 (2H, dd), 7.35 (1H, dd), 7.20 (1H, d), 6.74 (1H, d), 4.6 (2H, t), 4.2 (2H, t), 3.83 (3H, S), 3.76 (1H, m), 5.52 (4H, m), 3.33 (4H, s), 1.78 (4H, m), 1-32-1.16 (4H, m).

D) Synthesis of 3-[[4-[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-guinolinecarbonyloxy]-3-methoxy]phenyl]-2-propenoic acid 4-(nitrooxybutyl)butyl ester nitrate salt

To a solution of 3-[[4-[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarbonyloxy]-3-methoxy]phenyl]-2-propenoic acid 4-(nitrooxybutyl)butyl ester hydro chloride (2 g, 3.03 mmoles) in THF (20 ml) was added silver nitrate (514 mg, 3.03 mmoles). After stirring for 1 hours at room temperature, the mixture was filtered and the precipitate washed with THF and dried to afford 3-[4-[1-Cycylopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarbonyl oxy]-3-methoxy]2-propenoic acid 4-(nitrooxybutyl)butyl ester nitrate salt (2 g) as an amorphous solid. Yield 96%.

Elementary Analysis: % C % H % N % F Calculated: 54.78 5.17 9.98 2.71 Found: 54.69 5.15 9.99 2.69

Example 19

Synthesis of 4-(nitrooxy)butanoic Acid 2-methyl-5-nitro imidazole-1-ethyl ester nitrate salt

A) Synthesis of 4-bromobutanoic acid 2-methyl-5-nitro imidazole-1-ethyl ester

To a solution of metronidazole (7.5 g, 48.82 mmoles) in CHCl₃ (75 ml) and DMF (93 ml) 4-bromobutyrric acid (6.1 g, 36.51 mmoli) was added. After stirring the mixture for 24 hours at room temperature, the organic phase was washed with water, dried with sodium sulphate and evaporated under a reduced pressure.

The residue was purified by chromatography on a silica gel column eluted with metilene chlorid/acetone (v/v 9/1) to afford 4-Bromobutanoic acid 2-methyl-5-nitroimidazole-1-ethyl ester (6.5 g, 20.3 mmoles). Yield 55%.

B) Synthesis of 4-(nitrooxy)butanoic acid 2-methyl-5-nitro imidazole-1-ethyl Ester

To a solution of 4-bromobutanoic acid 2-methyl-5-nitro imidazole-1-ethyl ester (6.4 g, 20.05 mmoles) in anhydrous acetonitrile (170 ml) silver nitrate (5.11 g, 30.07 mmoles) was added The mixture was heated at 40° C. for 48 hours in the darkness. The mixture was filtered and the filtrate was washed with water, dried with sodium sulphate and evaporated in vacuo.

The residue was purified by chromatography on a silica gel column by eluting with metilene chloride/acetone (v/v 9/1) to afford 4-(nitrooxy)butanoic acid 2-methyl-5-nitroimidazole-1-ethyl ester (3.68 g, 12.17 mmoli) as an oil. Yield 60%.

¹H NMR (DMSO) ppm: 8.08 (1H, s); 4.55 (2H, t); 4.53 (2H, t) 4.43 (2H, t); 2.51 (2R, s); 2.40 (2H, t); 1.91 (2H, m).

C) Synthesis of 4-(nitrooxy)butanoic acid 2-methyl-5-nitro imidazole-1-ethyl ester nitrate salt

To a solution of 4-(nitrooxy)butanoic acid 2-methyl-5-nitroimidazole-1-ethyl ester (3.68 g, 12.17 mmoles) in CH₂Cl₂ (80 ml) was added HCl—AcOEt 1M (12.2 ml). After stirring for 1 hour at room temperature, the solvent was evaporated under a reduced pressure and the residue was dissolved in THF (75 ml). Silver nitrate (2 g, 12.17 mmoles) was added. The mixture was stirred for 1 hour at room temperature, the suspension filtered and the precipitate washed with THF and dried to afford 4-(nitrooxy)butanoic acid 2-methyl-5-nitroimidazole-1-ethyl ester nitrate salt (4.2 g) solid. Yield 90%.

Elementary Analisys: % C % H % N Calculated: 31.50 3.96 18.37 Found: 31.45 3.90 18.29

Example 20

Synthesis of 4-(nitrooxy)butanoic Acid 5-nitro-8-quinolinol ester nitrate salt

A) Synthesis of 4-bromobutanoic acid 5-nitro-8-quinolinol ester

To a solution of nitroxoline (4.32 g, 22.72 mmoles) and triethylamine (2.75 g, 27.26 mmol) in CHCl₃ (100 ml) and DMF (69 ml) 4-bromobutyrrilchloride (5.05 g, 27.26 mmoles) was added at 0° C. After stirring at room temperature for 24 hours, another portions of triethylamine (0.46 g, 4.5 mmol) and 4-bromobutyrril chloride (0.83 g, 4.5 mmoles) were added. The mixture was stirred for 48 hours at room temperature. Water and metilene chloride were added and, after separation of the two phases the organic layer was washed with water, dried with sodium sulphate and evaporated under a reduced pressure.

The residue was purified by chromatography on silica gel column eluted with ethyl acetate/n-hexane (v/v 2/8) to afford 4-bromobutanoic acid 5-nitro-8-quinolinol ester (6.86 g, 20.22 mmoles) as an oil. Yield 90%.

¹H NMR (CDCl₃) ppm: 9.06 (2H, m); 8.44 (1H, d); 7.65 (1H, m); 7.5 (1H, d); 3.66 (2H, m); 3.03 (2H, m); 2.42 (2H, m).

B) Synthesis of 4-(nitrooxy)butanoic acid 5-nitro-8-quinolinol ester

To a solution of 4-bromobutanoic acid 5-nitro-8-quinolinol ester (6.86 g, 20.2 mmoles) in anhydrous acetonitrile (100 ml) silver nitrate (13.65 g, 80.3 mmoles) was added. The mixture was heated at 40° C. for 64 hours in the darkness. The mixture was then filtered, the filtrate dried with sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column eluted with ethyl acetate/n-hexane (v/v 3/7) to afford 4-(nitrooxy)butanoic acid 5-nitro-8-quinolinol ester (2.05 g, 6.38 mmoles) as an yellow amorphous solid. Yield 31%. (m.p.=68° C.).

¹H NMR (DMSO) ppm: 9.02 (1H, dd); 8.97 (1H, d); 8.45 (1H, dd); 7.65 (1H, m); 7.54 (1H, dd); 4.74 (2H, t); 2.97 (2H, t); 2.03 (2H, m).

C) Synthesis of 4-(nitrooxy)butanoic acid 5-nitro-8-quinolinol ester nitrate salt

To a solution of 4-(nitrooxy)butanoic acid 5-nitro-8-quinolinol ester (2.05 g, 6.38 mmoles) in ethyl acetate (40 ml) was added HCl—AcOEt 1M (6.4 ml). After stirring for 1 hour at room temperature, the solvent was evaporated under a reduced pressure and the residue was dissolved in THF (50 ml) and added of silver nitrate (1.08 g, 6.38 mmoles). The mixture was stirred for 1 hour at room temperature, the suspension was filtered and the precipitate was washed with THF, dried to afford 4-(nitrooxy)butanoic acid 2-methyl-5-nitroimidazole-1-ethyl ester nitrate salt (2.2 g) solid. Yield 89%.

Elementary Analisys: % C % H % N Calculated: 39.01 3.22 13.99 Found: 38.94 3.14 13.91

Example 21

Synthesis of 6-(D-(−)-alfa-aminophenylacetamido)pennicillanic acid 4-(nitrooxy)butyl ester nitrate salt

A) Synthesis of 6-(D-(−)-alfa-aminophenylacetamido) pennicillanic sodium salt

To a solution of ampicillin (5.09 g, 14.6 mmoles) in absolute ethanol (120 ml) sodium ethylate (0.99 g, 14.6 mmoles) was added. The mixture was stirred for 1 hour at room temperature and then for at 60° C. 30 minutes. The mixture was evaporated under a reduced pressure to afford 6-(D-(−)-alfa-aminophenylacetamido)pennicillanic sodium salt (5.4 g, 14.5 mmoles) as a white solid. Yield 99%.

B) Synthesis of 6-(D-(−)-alfa-tert-butoxycarbonylaminophenyl acetamido) pennicillanic acid

To a solution of 6-(D-(−)-alfa-aminophenylacetamido) pennicillanic sodium salt (5.4 g, 14.57 mmoles) in 1,4-dioxane (166 ml) and water (121 ml), at a temperature of 0° C. a solution of di-tert-butyl dicarbonate (5.08 g, 23.31 mmoles) in 1,4-dioxane (45 ml) was added. When the addition was ended, the temperature was raised at room temperature and stirring was continued for 48 hours. The mixture was then evaporated under a reduced pressure. The residue was dissolved in aqueous NaHCO₃ 5%, washed with diethyl ether; the pH value of the aqueous phase was adjusted to the value of 2 by adding at a temperature of 0° C. H₃PO₄ 50% (11 ml). After extraction of the aqueous phase with ethyl acetate, the combined organic phases were dried and evaporated under a reduced pressure to afford 6-(D-(−)-α-tert-butoxycarbonylaminophenylacetamido) pennicillanic acid, that was used without further purification.

¹H NMR (CDCl₃) ppm: 7.34 (5H, s); 6.85 (1H, bs); 5.8 (1H, bs); 5.6 (1H, dd); 5.45 (1H, d); 5.22 (1H, bs); 4.38 (1H, s); 1.4 (15H, m).

B) Synthesis of 6-(D-(−)-alfa-aminophenylacetamido) pennicillanic acid 4-bromobutyl ester

To a solution of 6-(D-(−)-alfa-tert-butoxycarbonyl aminophenylacetamido)pennicillanic acid (6.36 g, 14.15 mmoles) in DMF (60 ml) triethylamine (2.76 ml, 19.81 mmoles) was added. After stirring for 30 minutes, 1,4-dibromobutane (6.11 g, 28.30 mmoles) was added and the mixture stirred for 12 hours.

Diethyl ether was then added at the suspension and Et₃N.HBr was filtered off. The organic phase was washed with water, dried with sodium sulphate and evaporated under a reduced pressure.

The residue was purified by chromatography on silica gel column eluted with ethyl acetate/n-hexane (v/v 15/85) to afford 6-(D-(−)-alfa-aminophenylacetamido)pennicillanic acid 4-bromo butyl ester (3.2 g) as a white solid.

¹H NMR (CDCl₃) ppm: 7.35 (5H, m); 6.6 (1H, bs); 5.6 (1H, m); 5.4 (1H, d); 5.2 (1H, bs); 4.39 (1H, s), 4.18 (2H, m); 3.42 (2H, t); 1.9 (4H, m); 1.4 (15H, m).

C) 6-(D-(−)-alfa-aminophenylacetamido)pennicillanic acid 4-nitrooxy butyl ester

To a solution of 6-(D-(−)-alfa-aminophenylacetamido) pennicillanic acid 4-bromobutyl ester (3.12 g, 5.34 mmoles) in acetonitrile (50 ml) silver nitrate (1.27 g, 7.48 mmoles) was added. The mixture was heated at 40° C. for 10 hours in the darkness. Then mixture was filtered and evaporated under a reduced pressure. The residue was purified by chromatography on a silica gel column by eluting with ethyl acetate/n-hexane v/v 3/7) to afford 6-(D-(−)-alfa-aminophenylacetamido) pennicillanic acid 4-nitrooxybutyl ester (0.9 g) as a yellow amorphous solid.

¹H NMR (CDCl₃) ppm: 7.35 (5H, m); 6.6 (1H, bs); 5.6 (1H, m); 5.4 (1H, m); 5.2 (1H, bs); 4.5 (2H, m); 4.4 (1H, s); 4.2 (2H, m); 1.8 (4H, bs); 1.4 (15H, m).

D) 6-(D-(−)-alfa-aminophenylacetamido)pennicillanic Acid 4-nitro Oxy Butyl Ester Nitrate Salt

To a solution of 6-(D-(−)-alfa-aminophenylacetamido) pennicillanic acid 4-nitrooxybutyl ester (0.9 g, 1.58 mmoles) in ethyl acetate (10 ml) a solution HCl 1M in AcOEt (1.5 ml) was added at 0° C. The mixture was stirred at 0° C. for 20 minutes and for 1 hour at room temperature. The solvent was evaporated under a reduced pressure, the residue dissolved in THF (5 ml) and the solution added of silver nitrate (268 mg, 1.58 mmoles). The mixture was stirred for 1 hour at room temperature, then filtered, and the precipitate washed with THF and dried to afford 6-(D-(−)-alfa-aminophenylacetamido)pennicillanic acid 4-nitrooxybutyl ester nitrate salt (736 mg) solid. Yield 88%.

Elementary Analisys: % C % H % N % S Calculated: 45.36 5.14 13.22 6.05 Found: 45.28 5.08 13.16 5.97

TABLE 1 Strain E. Coli (ATCC25922): Antimicrobial activity of Cefazolin and Cefazolin nitrate salt, Ampicillin and Ampicillin nitrate salt. CONCENTRATION COMPOUND (μg/ml) RESPONSE Cefazolin 0.5 Growth Cefazolin.HNO₃ 0.5 No growth Ampicillin 1.0 Growth Ampicillin.HNO₃ 1.0 No growth

TABLE 2 Strain S. Aureus (ATCC29213) Antimicrobial activity of Clindamycin and Clindamycin nitrate salt, Ciprofloxacin and Ciprofloxacin nitrate salt, Sulfamethoxazole and Sulfamethoxazole nitrate salt, Trimethoprim and Trimethoprim nitrate salt, Erythromycin and Erythromycin nitrate salt. CONCENTRATION COMPOUND (μg/ml) RESPONSE Clindamycin 0.03 Growth Clindamycin.HNO₃ 0.03 No growth Ciprofloxacin 0.05 Growth Ciprofloxacin.HNO₃ 1.0 No growth Sulfamethoxazole 20 Growth Sulfamethoxazole.HNO₃ 20 No growth Trimethoprim 0.5 Growth Trimethoprim.HNO₃ 0.5 No growth Erythromycin 0.06 Growth Erythromycin.HNO₃ 0.06 No growth 

What is claimed is:
 1. A nitrate salt of an antimicrobial compound having formula II:

wherein: X and Y, different from one another, are C or N, R₆=cyclopropyl, C₂H₅, 4-fluorophenyl, 2,4-difluorophenyl, or 2-fluoroethyl, R₇=H; amino, or CH₃, R₈=H or F, or when Y=N, R₈ is the free electron doublet on the nitrogen atom, which forms a double bond with the carbon atom adjacent the nitrogen, R₉=H or CH₃ or one of the following substituents:

wherein M=H, CH₃, C₂H₅, OH,

wherein T₁ is H, OH

R₈ and R₉ taken together form the bivalent radical having formula: —O—CH₂—O—  (IIP), R₁₀=H, Cl, F, or when X=N, R₁₀ is the free electron doublet on the nitrogen atom, which forms a double bond with the carbon atom adjacent the nitrogen, or R₈ and R₁₀ taken together form the following bivalent radicals:


2. The nitrate salt according to claim 1, selected from the following: when R₆=cyclopropyl, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=H, X=Y=C, the compound is known as Ciprofloxacin, when R₆=cyclopropyl, R₇=H, R₈=F, R₉=(IIF), R₁₀=Cl, X=Y=C, the compound is known as Clinaloxacin, when R₆=4-fluorophenyl, R₇=H, R₈=F, R₉=(IID), R₁₀=H, X=Y=C, the compound is known as Difloxacin, when R₆=C₂H₅, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=free valence, X=N, Y=C, the compound is known as Enoxacin, when R₆=cyclopropyl, R₇=H, R₈=F, R₉=(IIA) with M=C₂H₅, R₁₀=H, X=Y=C, the compound is known as Enrofloxacin, when R₆=fluoroethyl, R₇=H, R₈=F, R₉=(IIA) with M=CH₃, R₁₀=F, X=Y=C, the compound is known as Fleroxacin, when R₆ with R₁₀ forms the bivalent radical (IIM), R₇=H, R₈=F, R₉=H, X=Y=C, the compound is known as Flumequine, when R₆=cyclopropyl, R₇=CH₃, R₈=F, R₉=(IIB), R₁₀=H, X=Y=C, the compound is known as Gre-pafloxacin, when R₆=ethyl, R₇=H, R₈=F, R₉=(IIB), R₁₀=F, X=Y=C, the compound is known as Lomefloxacin, when R₆ with R₁₀ forms the bivalent radical (IIM), R₇=H, R₈=F, R₉=(IIE) with T₁=OH, X=Y=C, the compound is known as Nadifloxacin, when R₆=C₂H₅, R₇=H, R₈=H, R₈=CH₃, R₁₀=free valence, X=N, Y=C, the compound is known as Na-lidixic Acid, when R₆=C₂H₅, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=H, X=Y=C, the compound is known as Norfloxacin, when R₆ with R₁₀ forms the bivalent radical (IIN), R₇=H, R₈=F, R₉=(IIA) with M=CH₃, X=Y=C, the compound is known as Ofloxacin, when R₆=C₂H₅, R₇=H, R₈ and R₉ form the bivalent radical (IIP), R₁₀=H, X=Y=C, the compound is known as Oxolinic Acid, when R₆ with R₁₀ forms the bivalent radical (IIO), R₇=H, R₈=F, R₉=(IIH), X=Y=C, the compound is known as Pazufloxacin, when R₆=ethyl, R₇=H, R₈=F, R₉=(IIA) with M=CH₃, R₁₀=H, X=Y=C, the compound is known as Pefloxacin, when R₆=C₂H₅, R₇=H, R₈=free valence, R₉=(IIA) with M=H, R₁₀=free valence, X=Y=N, the compound is known as Pipemidic Acid, when R₆=C₂H₅, R₇=H, R₈=free valence, R₉=(IIE) with T₁=H, R₁₀=free valence, X=Y=N, the compound is known as Piromidic Acid, when R₆ with R₁₀ forms the bivalent radical (IIQ), R₇=H, R₈=F, R₉=(IIA) with M=CH³, X=Y=C, the compound is known as Rufloxacin, when R₆=cyclopropyl, R₇=amino, R₈=F, R₉=(IIC), R₁₀=F, X=Y=C, the compound is known as Sparfioxacin, when R₆=2,4-difluorophenyl, R₇=H, R₈=F, R₉=(IIE), R₁₀=free valence, X=N, Y=C, the compound is known as Tosufloxacin, when R₆=2,4-difluorophenyl, R₇=H, R₈=F, R₉=(IIG), R₁₀=free valence, X=N, Y=C, the compound is known as Trovafloxacin, when R₆=cyclopropyl, R₇=H, R₈=F, R₉=(IID), R₁₀=H, X=Y=C, the compound is known as Danofloxacin, or when R₆=4-fluorophenyl, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=H, X=Y=C, the compound is known as Sarafloxacin.
 3. The nitrate salt according to claim 2 selected from the following: when R₆=cyclopropyl, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=H, X=Y=C, the compound is known as Ciprofloxacin, when R₆=C₂H₅, R₇=H, R₈=H, R₉=CH₃, R₁₀=free valence, X=N, Y=C, the compound is known as Nali-dixic acid, when R₆=C₂H₅, R₇=H, R₈=F, R₉=(IIA) with M=H, R₁₀=H, X=Y=C, the compound is known as Norfloxacin, or when R₆ with R₁₀ forms the bivalent radical (IIN), R₇=H, R₈=F, R₉=(IIA) with M=CH₃, X=Y=C, the compound is known as Ofloxacin.
 4. The nitrate salt according to claim 1 wherein in their molecules there are one or more substituents having the formula (I-N) —B—(W)_(p)—ONO₂  (I-N) wherein: p is 1 or 0; B=—T_(B)—Y—T_(BI)— wherein T_(B) and T_(BI) are same or different; T_(B) is a chemical function covalently linked to the chemical or reacting function of the drug molecule and is (CO) or X, wherein X=O, S, NH, with the condition that X=(CO) when the reacting function of the drug is OH or NH₂ or SH; T_(B) is X when the reacting function of the drug is a carboxyl group; T_(BI)=(CO)_(tx) or (X)_(txx), wherein tx and txx are 0 or 1; with the condition that tx=1 when txx=0, tx=0 when txx=1; X is as above defined; Y is a bivalent linking bridge chosen between the following structures:

 wherein: nIX is an integer selected from 0, 1, 2, or 3; nIIX is an integer selected from 0, 1, 2, or 3; R_(TIX), R_(TIX), R_(TIIX), R_(TIIX′), same or different each from the other, are H or linear or branched C₁-C₄ alkyl; Y³ is a ring containing at least one salifiable nitrogen atom; an alkylene group R′ wherein R′ is a linear or branched C₁-C₂₀ alkyl, optionally substituted with one or more of the following groups: —NHCOR_(3Y), wherein R_(3Y) is a linear or branched C₁-C₅ alkyl, —NH₂, or —OH, a cycloalkylene ring C₅-C₇, optionally substituted with R′, being R′ as above defined, wherein one or more C atoms of the cycloalkylene can be optionally substituted with heteroatoms;

 wherein n3 is an integer from 0 to 3 and n3′ is an integer from 1 to 3;

 wherein n3 and n3′ have the meanings above indicated;

 wherein: R_(4Y) is OH, or H, alcoxy R_(5Y)O— wherein R_(5Y) is a linear or branched or cyclo C₁-C₁₀ alkyl; R_(2Y) is a linear or branched alkenylene C₂-C₁₀ containing one or more double bonds;

 wherein R_(1f)=H, CH₃ and nf is an integer from 0 to 6; W of formula (I-N) is the bivalent radical —T_(C)—Y_(T)-wherein: T_(c)=(CO) when t_(x)=0, T_(c)=X when t_(xx)=0; with the proviso that in formula (I-N) when p=1 Y_(T) is different from Y and in the bivalent radical B: Y is R′ as above defined having a substituent NHCOR_(3Y), or Y is a bivalent radical of formula (V-Y), wherein R_(4Y) is OR_(5Y) and R_(5Y) is CH₃, R_(2Y) is the group —CH═CH—.
 5. The nitrate salt according to claim 4 wherein Y³ in formula (II-Y) is selected from the following bivalent radicals:


6. The nitrate salt according to claim 5 wherein Y³ is a 6-membered aromatic ring containing one nitrogen atom, said ring having the two free valences in the following positions: 2,6; 2,3; or 2,5.
 7. The nitrate salt according to claim 6 wherein Y³ is Y12 substituted at positions 2 and
 6. 8. A composition comprising the nitrate salt according to claim 1 wherein one or more isomers of the compounds are included.
 9. The nitrate salt according to claim 1 containing one nitrate ion mole/compound mole.
 10. The nitrate salt according to claim 1 containing one substituent of the formula (I-N).
 11. The nitrate salt according to claim 4 wherein R_(TIX), R_(TIX′), R_(TIIX), and R_(TIIX′) are H.
 12. The nitrate salt according to claim 4, wherein Y is a heterocyclic ring containing one or two nitrogen atoms, the ring saturated, unsaturated or aromatic.
 13. The nitrate salt according to claim 4, wherein the ring has 5 or 6 atoms.
 14. The nitrate salt according to claim 4, wherein R′ is a C₂-C₆ alkyl and/or R_(5Y) is methyl.
 15. The nitrate salt according to claim 4, wherein R_(2Y) is an ethylene group (—CH—CH).
 16. The nitrate salt according to claim 4, wherein nf is an integer from 0 to
 4. 17. The nitrate salt according to claim 4, wherein in formula (I-N) when p=1 Y_(T) is different from Y and in the bivalent radical B: R′ is a C₂ saturated alkyl and R_(3Y) is CH₃.
 18. The nitrate salt according to claim 4, wherein in formula (I-N) when p=1 Y_(T) is different from Y and in the bivalent radical B: Y is CH₂—CH(NHCOCH₃)— and B in formula (I-N) has the following structure:


19. The nitrate salt according to claim 4, wherein in formula (I-N) when p=1 Y_(T) is different from Y and in the bivalent radical B: Y has the following formula:


20. A pharmaceutical composition, comprising a compound having formula II:

wherein: X and Y, different from one another, are C or N, R₆=cyclopropyl, C₂H₅, 4-fluorophenyl, 2,4-difluorophenyl, or 2-fluoroethyl, R₇=H, amino or CH₃, R₈=H or F, or when Y=N, R₈ is the free electron doublet on the nitrogen atom, which forms a double bond with the carbon atom adjacent the nitrogen, R₉=H, CH₃ or one of the following substituents:

wherein M=H, CH₃, C₂H₅, or OH,

wherein T₁ is H, OH

R₈ and R₉ taken together form the bivalent radical having formula: —O—CH₂—O— (IIP), R₁₀=H, Cl, or F, or when X=N, R₁₀ is the free electron doublet on the nitrogen atom, which forms a double bond with the carbon atom adjacent the nitrogen, or R₆ and R₁₀ taken together form the following bivalent radicals:

and a pharmaceutical carrier. 